Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT

Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [ 64 Cu]copper PET/CT Kristoffer Kjærgaard, Thomas Damgaard Sandahl, Kim Frisch, Karina Højrup Vase, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-23655/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Jun, 2020 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 2 posted 4 You are reading this latest preprint version Show more versions Abstract Purpose: Copper is essential for enzymatic processes throughout the body. [ 64 Cu]copper ( 64 Cu) positron emission tomography (PET) has been investigated as a diagnostic tool for certain malignancies, but has not yet been used to study copper homeostasis in humans. In this study, we determined the hepatic removal kinetics, biodistribution and radiation dosimetry of 64 Cu in healthy humans by both intravenous and oral administration. Methods: Six healthy participants underwent PET/CT studies with intravenous or oral administration of 64 Cu. A 90 min dynamic PET/CT scan of the liver was followed by three whole-body PET/CT scans at 1.5, 6, and 20 h after tracer administration. PET data were used for estimation of hepatic kinetics, biodistribution, effective doses, and absorbed doses for critical organs. Results: After intravenous administration, 64 Cu uptake was highest in the liver, intestinal walls and pancreas; the gender-averaged effective dose was 62 ± 5 μSv/MBq (mean ± SD). After oral administration, 64 Cu was almost exclusively taken up by the liver while leaving a significant amount of radiotracer in the gastrointestinal lumen, resulting in an effective dose of 113 ± 1 μSv/MBq. Excretion of 64 Cu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of 64 Cu from blood was 0.10 ± 0.02 mL blood/min/mL liver tissue, and the rate constant for excretion into bile or blood was 0.003 ± 0.002 min -1 . Conclusion: 64 Cu biodistribution and radiation dosimetry are influenced by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration, and after oral administration, 64 Cu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq 64 Cu yielded images of high quality for both administration forms with radiation doses approximately 3.1 and 5.7 mSv, respectively, allowing for sequential studies in humans. Trial Registration Number: EudraCT no. 2016-001975-59. Registration date: 19/09/2016. Nuclear Medicine & Medical Imaging 64Cu copper kinetics dosimetry biodistribution Figures Figure 1 Figure 2 Figure 3 Introduction Copper is an essential mineral present in all tissues and is important for several enzymatic processes [1]. It is absorbed in the upper intestine and taken up by the liver via the portal vein. From the liver, copper is either distributed to the systemic circulation bound to ceruloplasmin or, in the case of excess, excreted into the bile [2]. Disturbances in copper homeostasis are potentially fatal as seen in the rare genetic disorder of Wilson’s disease, where accumulation of toxic levels of copper in various organs leads to critical symptoms from the liver and central nervous system [3]. Human copper metabolism and kinetics are only partly understood despite recent advances in molecular imaging, notably positron emission tomography (PET). [ 64 Cu]copper [1] ( 64 Cu) PET is characterized by high spatial resolution (positron range, 0.7 mm in water), and the radioactive half-life of 64 Cu ( t 1/2 = 12.7 h) allows for in vivo assessment of copper biodistribution, even in compartments with slow copper turnover [4]. To date, only few 64 Cu PET studies of biodistribution and radiation dosimetry after intravenous injection in humans have been published, but it remains unclear which organs are the most critical in terms of radiation exposure [5-7]. In addition, no such studies have been published with oral administration of 64 Cu, the natural entrance route of copper in humans. 64 Cu PET/CT has been used in the context of cancer detection and characterization [6-9], utilizing the overexpression of the human copper transporter 1 (CTR1) in malignant cells [10]. To our knowledge, no studies have yet examined the potential of 64 Cu PET/CT to assess temporal whole-body copper homeostasis in humans, in particular hepatic copper uptake, accumulation and excretion. In this study, we determined the hepatic kinetics of 64 Cu, characterized copper biodistribution and estimated the radiation dosimetry of 64 Cu in healthy humans by sequential whole-body PET imaging spanning 1.5 to 20 h after intravenous as well as oral administration. The image based biodistribution estimates were supplemented by measurements of radioactive concentrations in blood, urine and faecal samples. [1] In vivo 64 Cu-ions exist in different oxidation states and with various exchangeable counter-ions. Throughout this paper, these 64 Cu-labelled species are referred to collectively as “ 64 Cu”. Materials And Methods Radiochemistry Cyclotron-produced 64 Cu (nuclear reaction: 64 Ni(p,n) 64 Cu) was obtained from a commercial source (the Hevesy Laboratory, DTU Nutech, Risø, Roskilde, Denmark) and delivered to our centre as solid 64 CuCl 2 (radionuclidic purity ≥ 99 %; specific activity ≥ 1.0 TBq/µmol) on the day of the study (one batch production of 64 CuCl 2 was used over two days for two or three participants). Before use, the received 64 CuCl 2 was dissolved in sterile 0.1 M HCl (1 mL), pH was adjusted to around 5 with sterile 0.5 M sodium acetate buffer (0.5 mL), and sterile saline (8.5 mL) was added. The acetate buffered 64 Cu solution was finally passed through a sterilizing filter (0.22 µm) into a sterile product vial. Quality control of the 64 Cu solution consisted of pH measurement (pH strips; specification: 4-6), radiochemical purity test (radio-TLC; specification: ≥95%), LAL-test (PTS Endosafe, Charles River Laboratories; specification: <17.5 EU/ml), radionuclide identification (gamma spectrum; germanium detector; specification: 511 + 1346 keV), and sterile filter test (pressure-hold-test; specification: filter intact). The preparation and quality control of the 64 Cu solution was approved by the Danish Medicines Agency. Study Design and Participants Biodistribution and dosimetry for 64 Cu after intravenous and oral administration were determined by dynamic liver and subsequent whole body PET/CT in six healthy human participants (age 22-61 years). Four participants received intravenous administration (IV1-IV4; two males, two females) and two received oral administration (O1-O2; one male, one female) of 64 Cu (Table 1). In an additional four participants (IV5-IV8; 2 males, two females) blood, urine, and faecal samples were collected after intravenous 64 Cu administration, but without PET imaging (Supplemental Table 1). Participants fasted for at least 6 h before administration of 64 Cu, but were allowed to drink water. Study inclusion criteria were: Age above 18 years, and for females, negative pregnancy test and use of safe contraception. Criteria for exclusion were known hypersensitivity to ingredients in the formula, use of drugs that affect copper metabolism, history of clinical disease, current pregnancy, breastfeeding, or desire to become pregnant. No complications to the procedures were observed. IV Oral ID (sex/age) IV1 (M/61)* IV2 (F/25) IV3 (M/24) IV4 (F/22) O1 (F/39) O2 (M/27) BW/height (kg/cm) 76/178 74.7/175 94/186 68/160 54/168 77/181 Dose (MBq) 116.4 66.04 73.0 77.0 57.3 61.3 Target organ Liver 415.0 467.0 462.0 446.0 317.0 335.0 Gallbladder 87.8 108.0 126.0 68.4 144.0 119.0 Stomach 48.3 61.1 58.0 48.8 274.0 238.0 Small Intestine 188.0 238.0 191.0 168.0 369.0 395.0 RLI 225.0 88.7 181.0 213.0 925.0 600.0 LLI 250.0 87.1 120.0 121.0 30.4 375.0 Kidneys 137.0 128.0 133.0 132.0 66.0 72.6 Pancreas 116.0 122.0 110.0 173.0 51.8 51.5 Red Bone Marrow 36.2 34.0 35.5 32.5 27.0 24.4 Effective Dose 67.6 56.2 62.0 61.3 114.0 112.0 Table 1 Participant characteristics, gender-averaged absorbed dose estimates (µGy/MBq), and effective dose (µSv/MBq) for 64 Cu by intravenous (IV) and oral administration Data for critical target organs and effective doses for all individuals are displayed; for full list of organs, see Supplemental Table 3. *Dynamic PET/CT scan and blood samples not obtained. Abbreviations: BW = Body Weight; RLI = Right Large Intestine; LLI = Left Large Intestine. PET/CT Acquisition The participants were placed in supine position in a Siemens Biograph TM 64 TruePoint TM PET/CT camera within the 21.6 cm axial field-of-view. A low dose CT scan (50 effective mAs with CARE Dose4D, 120 kV, pitch of 0.8 mm, slice thickness 5.0 mm) was performed before each PET scan for definition of anatomic structures and attenuation correction of the PET images. The 64 Cu solution was administered as an intravenous bolus injection (n = 4; median dose 73.5 MBq, range 66-116 MBq) or dissolved in water and swallowed (n = 2; median dose 65.5 MBq, range 57–74 MBq). All participants underwent a dynamic PET scan of 90 min (dynamic PET and blood sampling were not acquired for one participant, see Table 1) with field-of-view over the liver, recorded in list-mode; time frame structure was 12x5 s, 8x15 s, 7x60 s, and 16x300 s. This was followed by three consecutive whole-body PET/CT scans (top of skull to mid-thigh; 6 bed positions) performed at 1.5, 6, and 20 h after tracer administration (duration 6, 6, and 10 min per bed position). The PET images were reconstructed using 3-dimensional ordered-subset expectation maximization with 4 iterations and 21 subsets, 4-mm Gauss filter, and 168x168 matrix with voxel size 4x4x5mm 3 . Image Processing The fused PET/CT images were analysed using the PMOD 3.7 software (PMOD Technologies Ltd, Zürich, Switzerland). For kinetic analysis, the time course of the activity concentration of 64 Cu during the 90-min dynamic PET scan was measured in a volume-of-interest (VOI) placed in the right liver lobe. The VOIs were drawn to contain liver tissue while avoiding large intrahepatic blood vessels and bile ducts. For biodistribution and dosimetry calculations, all tissues were visually inspected on images of the 1.5 h, 6 h, and 20 h whole body scans by two investigators. Organs with accumulation of 64 Cu above that of surrounding tissue were defined as source organs: liver, gallbladder contents, small intestine, left large intestine (descending and sigmoid colon), right large intestine (ascending and transverse colon), rectum, stomach contents, kidneys, pancreas (IV only), and red bone marrow. VOIs were manually drawn for each source organ to encompass all radioactivity of the respective organ. The red bone marrow activity was estimated based on VOIs in the lumbar vertebrae as described by McParland [11]. Blood, Urine and Faecal Samples In the intravenous study, arterial blood samples were collected from a radial artery during the initial dynamic PET scan at time points 12x5 s, 8x15 s, 7x60 s, and 16x300 s. In the oral study, venous blood samples were collected from a peripheral vein during the initial dynamic PET scan and before each of the consecutive whole-body scans (1.5 h, 6 h, and 20 h). In additional four participants with intravenous tracer administration (IV5-8), venous blood samples were obtained as for the oral study, and total urine and faeces were collected from 0-6 h and 6-20 h. Radioactivity concentrations of 64 Cu were measured in whole blood, plasma, urine, and faeces using a well gamma counter (Packard 5003, Packard Instruments, USA). Time courses of the activity concentration in blood and plasma were generated for 90 min with two additional samples at 6 h and 20 h. Total output in percent of administered dose (%AD) for urine and faeces were calculated for time points 6 h and 20 h. All concentration measurements were cross-calibrated with the PET-camera and corrected for radioactive decay back to start of the tracer administration. Prior to the injection of radiotracer, a venous blood sample was drawn for measurement of baseline blood tests of liver and kidney function, haematological quantities, and copper metabolism. Modelling of Hepatic Kinetics Kinetic parameters were estimated by fitting kinetic models to the dynamic liver PET data using the time course of arterial plasma 64 Cu as input function. To account for the hepatic dual blood supply from the hepatic artery (25%) and portal vein (75%), we used reversible linearised models that allow robust and unbiased estimates using only the arterial input function [12]. Two kinetic models were used: 1) The Gjedde-Patlak linearisation yielding the steady-state clearance from blood to liver tissue ( K ; mL blood/min/mL liver tissue) including a small reversible loss rate constant ( k loss ; min -1 ), representing the loss of tracer from the liver hepatocytes into bile or blood [13]; 2) the Logan linearisation [14] that estimates the total distribution volume ( V d ; mL blood/mL liver tissue) of 64 Cu in the liver. Both kinetic models were applied to data 30 to 90 min after tracer administration to ensure quasi-steady-state. The kinetic model parameters were estimated using software developed in-house (Supplemental Figure 1). Biodistribution and Dosimetry For each source organ, the time course of the non-decay-corrected total radioactivity was normalised to the administered activity and recalculated to time courses of percentage injected activity. Time-integrated activity coefficients (TIACs) were computed using the trapezoidal integration method to calculate the area under the curves, assuming only physical decay after the last scan without further biological clearance. The remainder TIAC was calculated by subtracting the individual source organ TIACs from the total body TIAC (without voiding), which for 64 Cu is 18.3 h. TIACs for source organs and remainder were used in OLINDA/EXM 2.0 (HERMES Medical Solution AB, Sweden) [15] to compute organ absorbed doses (μGy/MBq) and the effective dose (μSv/MBq) using anthropomorphic human body phantoms with organ masses based on ICRP89 [16] and ICRP103 tissue weighting factors [17]. Organ doses and effective dose results are given for the reference gender-averaged adult according to ICRP103. Results Biodistribution Figures 1 and 2A-B show whole-body PET/CT and time-activity curves for the biodistribution of 64 Cu. 64 Cu was avidly taken up by the liver after both intravenous and oral administration with the highest concentrations reached after 6 h, where %AD in the liver was 47 ± 1.35 % and 34 ± 0.01 % (mean ± SD), respectively. In addition, radioactivity was observed in the red bone marrow and kidneys. Uniquely for the intravenous administration, 64 Cu was taken up by the pancreas, intestinal walls, and salivary glands (Figure 1). After oral administration, the biodistribution of 64 Cu was dominated by efficient uptake by the liver and varying degrees of residual activity in the intestinal lumen. Approximately 1.5 h after administration for both groups, the variation in biodistribution between the participants was insignificant (Figure 2A-B). Accumulation of 64 Cu in other organs, including the brain, urinary bladder, and prostate was negligible. The hepatic uptake of 64 Cu was rapid after intravenous administration, whereas the uptake following oral administration was delayed (approximately 12 min) by the process of intestinal absorption (Figure 2C-D). Apart from the delay, the rate of uptake in liver tissue was comparable between the two administration forms with %AD in the liver peaking at 6 h followed by a minor decrease, most likely caused by biliary excretion and redistribution of 64 Cu back to blood. The gallbladder was visible on the PET images in five of the six participants after 1.5 h, indicating some degree of biliary excretion at this time. Hepatic Removal Kinetics Analysis of the hepatic removal kinetics of 64 Cu following intravenous administration provided robust linear model-fits to the liver PET data (examples in Supplemental Figure 1). The steady-state hepatic clearance of 64 Cu from blood into liver tissue ( K ) was 0.10 ± 0.02 mL blood/min/mL liver tissue with marginal loss of tracer into bile or blood ( k loss = 0.003 ± 0.002 min -1 ); the hepatic volume of distribution ( V d ) was 36 ± 22 mL blood/mL liver tissue (mean ± SD; n = 3). Blood, Urine and Faeces After intravenous administration, arterial 64 Cu was rapidly cleared from the systemic circulation; the whole-blood to plasma activity ratio was approximately 55%, increasing slowly during the initial 90 min (Figure 3A). The venous 64 Cu showed a similar pattern and increased slowly for the remaining study period (Figure 3B). After oral administration, venous blood concentrations increased until approximately 1 hour and then gradually subsided before a late slow increase, comparable to that observed after intravenous administration (Figure 3B). The low radioactivity concentration in venous blood following oral administration illustrates the efficient first-pass extraction of 64 Cu through the liver. After intravenous administration, insignificant amounts of 64 Cu were measured in urine (mean %AD ± SD: 0.0013 ± 0.0006) and faeces (median %AD [range]: 0.0022 [0.0002-0.0416]) during the study period (Supplemental Figure 2). Urine and faeces were not collected after oral administration. Baseline blood tests were all within normal range or near-normal (Supplemental Table 2). Radiation Dosimetry Participant characteristics and dosimetry data are given in Table 1; the full list of organs is given in Supplemental Table 3. After intravenous administration, the most critical organ was the liver (range 415-467 µGy/MBq), followed by the small intestines (range 168-238 µGy/MBq). After oral administration, the most critical organ was the right large intestine (range 600-925 µGy/MBq), followed by the small intestines (range 369-378 µGy/MBq), liver (range 317-335 µGy/MBq), and stomach (range 238-274 µGy/MBq). Importantly, the radiation exposure to the intestines was highly dependent on individual peristalsis and intestinal transit time as observed in participant O1, where the right large intestine received as much as 925 µGy/MBq and the left large intestine, almost nothing. In contrast, the radiation dose to the liver varied very little between the participants for both administration forms. The gender-averaged effective doses after intravenous and oral administration were 62 ± 5 and 113 ± 2 µSv/MBq (mean ± SD). Discussion In this study, we report 64 Cu PET/CT results on biodistribution, dosimetry, and hepatic removal kinetics following both intravenous and oral administration of the radiotracer in healthy humans. 64 Cu Biodistribution Following absorption in the intestines, copper is transported into the portal blood circulation by the ATP7A transporter located in the basolateral membrane of the enterocytes [18]. In the portal vein, copper is bound to albumin, in particular, and to other plasma proteins in a highly exchangeable pool [19, 20]. Albumin-bound copper in systemic plasma has a half-life of 10-20 min [21] and is effectively extracted during the hepatic first pass (>80%) [22]. In the present study, uptake of 64 Cu from the systemic circulation after intravenous administration was observed in tissues characterised by high expression of the CTR1 transporter such as the liver, pancreas, intestinal walls, and kidneys [23]. After intravenous administration, 64 Cu was not excreted in urine and only a negligible amount was detected in faeces during the 20-hour observation period. After oral administration, the biodistribution was dominated by the hepatic first pass extraction of 64 Cu, whereas uptake in organs other than the liver, kidneys, and red bone marrow was negligible when compared with intravenous administration. Moreover, the total %AD taken up from the intestines and measured in source organs did not exceed 50%, which is in accordance with net intestinal copper absorption studies in pigs and humans [20, 24]. It should be noted that the intestinal absorption of copper is affected by the dietary composition and our results therefore only reflect conditions in the 6 h fasting state [25]. In the liver, copper is incorporated in ceruloplasmin (biological half-life: 13 hours) and then redistributed into the systemic circulation 2-3 days after administration, creating a second peak in blood concentration, also known as the ceruloplasmin wave [26, 27]. In the present study, the blood concentration of 64 Cu steadily increased after the peak following administration, reflecting copper incorporation into ceruloplasmin. The arterial blood to plasma radioactivity ratio was approximately 55% and increased over the first 90 min, possibly reflecting copper uptake in erythrocytes by the anion exchanger located in the erythrocyte membrane [28]. 64 Cu Dosimetry Dosimetry estimates for intravenous administration of 64 Cu showed that the liver was the most critical organ, followed by the small intestines. Reports of dosimetry estimates for intravenous administration of 64 Cu differ to some extent. In the present study, radiation exposure to the liver and intestines was considerably higher and the effective dose twice of that previously reported in patients with prostate cancer [6, 7]. This difference is likely because of different analytical approaches rather than altered biodistribution of 64 Cu in patients with prostate cancer compared with healthy subjects. However, our results, based on the newest phantoms and tissue weighing factors [15-17], are in agreement with the observations made by Avila-Rodriguez et al. in healthy participants [5]. To our knowledge, dosimetry estimates for oral administration of 64 Cu have not previously been reported. As expected, the radiation dosimetry of 64 Cu after oral and intravenous administration differed significantly. While the liver was exposed to a high radiation dose after oral administration, equal or higher doses were received by the intestines due to high amounts of unabsorbed radiotracer. In this context, it is important to acknowledge that the radiation dose to the intestines depends on the individual intestinal transit time, unlike for intravenous administration; in our study, one participant received 925 µGy/MBq to the right large intestine. Consequently, the radiation dosimetry of 64 Cu by oral administration may differ substantially between individuals, necessitating a cautious approach to total oral dose used in future studies. Based on our results, the total radiation dose received by the reference gender-averaged adult after an oral ingestion of 50 MBq 64 Cu amounts to 5.6 mSv, ensuring less than 50 mSv absorbed by a single organ. This dose is sufficient to obtain high-quality PET images, and may still be reduced by at least 50% with new digital PET systems yielding faster time-of-flight timing resolution and higher NEMA sensitivity. Thus, 64 Cu PET using intravenous or oral administration is suitable for studying copper metabolism in humans. In this context, it is worth noting that because of the commercial availability and long half-life of the 64 Cu radioisotope, 64 Cu PET can be performed also at PET centres without the necessary facilities to produce 64 Cu. Copper Metabolism The use of radioactive Cu isotopes to assess copper metabolism in humans was introduced decades ago, and many studies on this topic have been published since then [29-32]. Most recently, Czlonkowska et al. showed that measurements of 64 Cu in blood and in urine following intravenous injection accurately distinguished between patients with Wilson’s disease and heterozygote controls [32]. The obvious advantage of 64 Cu-copper PET/CT is however, the potential for assessing also the hepatic uptake, accumulation, and turnover; this includes oral administration where the biodistribution is dominated by first pass extraction by the liver, as demonstrated in the present study. In addition, the PET/CT data on the accumulation of protein-bound 64 Cu reported in this study provides valuable knowledge to help interpret unwanted copper loss in relation to the increasing research on 64 Cu radiopharmaceuticals [33]. Peng et al. assessed hepatic copper kinetics in rats using 64 Cu PET/CT [34], revealing some noteworthy differences between rodents and our human participants. For example, cardiac uptake of 64 Cu was substantial in rodents whereas it was negligible in our human participants. Results from rodent copper studies can therefore not be easily translated to human conditions. In the present study, we were able to quantify the hepatic removal kinetics of 64 Cu using dynamic PET/CT with measurements of arterial 64 Cu concentration. The hepatobiliary excretion of 64 Cu is slower than e.g. bile acids [35], but importantly, the properties of the 64 Cu isotope allow for long-term studies of copper metabolism in humans. One of the primary therapeutic strategies in the treatment of Wilson’s disease is to inhibit absorption of dietary copper in order to reduce systemic and hepatic accumulation [3]. Because of the dominant hepatic first-pass extraction of copper following ingestion, the concentration of Cu in systemic blood may not be a reliable measure when assessing how well pharmaceuticals impair absorption of copper in the intestine. While intravenous administration of 64 Cu bypasses this first-pass metabolism, 64 Cu PET following oral administration proves useful for assessing the enterohepatic transport of copper in vivo . Moreover, since oral ingestion of 64 Cu reduces the invasiveness of the procedure, 64 Cu PET/CT with oral administration would be more suitable for clinical evaluation of copper metabolism in patients with Wilson’s disease. Conclusion For intravenous administration, the gender-averaged effective dose was 62 ± 5 µSv/MBq with the liver being the most critical organ. For oral administration, residual radiotracer in the gastrointestinal tract resulted in high radiation doses to the intestines, leading to an effective dose of 113 ± 1 µSv/MBq. We found that both intravenous and oral administrations of 50 MBq 64 Cu were sufficient for sequential studies in humans, yielding images of high quality up to 20 hours after administration with radiation doses of approximately 3.1 mSv and 5.7 mSv, respectively. Thus, 64 Cu PET/CT using intravenous and oral administration represent suitable methods for assessment of copper metabolism in humans, including the intestinal absorption, hepatic removal kinetics, and subsequent redistribution of copper. Declarations Acknowledgements: The authors would like to thank the participants for enrolling in this study as well as the staff from the Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, for experimental assistance. Author contributions: TS , SK , HV , PO , LG and OLM conceived the study. TS , SK and LG performed the experimental procedures and KF and KV were in charge of the radiochemistry. KK analysed data, performed statistical analyses and wrote the first draft of the manuscript together with TS , LG and OLM . All authors contributed to, read, and approved the final manuscript. Compliance with ethical standards: The study was approved by the Danish Medicines Agency (EudraCT no. 2016-001975-59) and the Central Denmark Region Committees on Health Research Ethics, conducted in accordance with the Helsinki II Declaration, and monitored by the Good Clinical Practice Unit (Aarhus University). Declarations: Funding: This study was supported by an unrestricted research grant from the Foundation of Manufacturer Vilhelm Pedersen and Wife. Conflicts of interest: The authors declare that they have no conflicts of interest. Consent for publication: All participants signed written informed consent for participation in the study and regarding publication of their data and images. Availability of data and material: The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. References Tapiero H, Townsend DM, Tew KD. Trace elements in human physiology and pathology. Copper. 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Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiological reviews. 1985;65:238-309. doi:10.1152/physrev.1985.65.2.238. Zhou B, Gitschier J. hCTR1: a human gene for copper uptake identified by complementation in yeast. Proceedings of the National Academy of Sciences of the United States of America. 1997;94:7481-6. doi:10.1073/pnas.94.14.7481. Turnlund JR, Keyes WR, Anderson HL, Acord LL. Copper absorption and retention in young men at three levels of dietary copper by use of the stable isotope 65Cu. The American journal of clinical nutrition. 1989;49:870-8. doi:10.1093/ajcn/49.5.870. Wapnir RA. Copper absorption and bioavailability. The American journal of clinical nutrition. 1998;67:1054s-60s. doi:10.1093/ajcn/67.5.1054S. Sternlieb I. Copper and the liver. Gastroenterology. 1980;78:1615-28. Marceau N, Aspin N. Distribution of ceruloplasmin- ceruloplasmin-bound 67 Cu in the rat. The American journal of physiology. 1972;222:106-10. doi:10.1152/ajplegacy.1972.222.1.106. Alda JO, Garay R. Chloride (or bicarbonate)-dependent copper uptake through the anion exchanger in human red blood cells. The American journal of physiology. 1990;259:C570-6. doi:10.1152/ajpcell.1990.259.4.C570. Sternlieb I, Scheinberg IH. Radiocopper in diagnosing liver disease. Seminars in nuclear medicine. 1972;2:176-88. Gunther K, Lossner V, Lossner J, Biesold D. The kinetics of copper uptake by the liver in Wilson's disease studied by a whole-body counter and a double labelling technique. European neurology. 1975;13:385-94. doi:10.1159/000114694. Harvey LJ, Dainty JR, Hollands WJ, Bull VJ, Beattie JH, Venelinov TI, et al. Use of mathematical modeling to study copper metabolism in humans. The American journal of clinical nutrition. 2005;81:807-13. doi:10.1093/ajcn/81.4.807. Czlonkowska A, Rodo M, Wierzchowska-Ciok A, Smolinski L, Litwin T. Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease. Liver international : official journal of the International Association for the Study of the Liver. 2018;38:1860-6. doi:10.1111/liv.13715. Zhou Y, Li J, Xu X, Zhao M, Zhang B, Deng S, et al. (64)Cu-based Radiopharmaceuticals in Molecular Imaging. Technol Cancer Res Treat. 2019;18:1533033819830758. doi:10.1177/1533033819830758. Peng F, Lutsenko S, Sun X, Muzik O. Imaging copper metabolism imbalance in Atp7b (-/-) knockout mouse model of Wilson's disease with PET-CT and orally administered 64CuCl2. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging. 2012;14:600-7. doi:10.1007/s11307-011-0532-0. Ørntoft NW, Munk OL, Frisch K, Ott P, Keiding S, Sørensen M. Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography. Journal of hepatology. 2017;67:321-7. doi:10.1016/j.jhep.2017.02.023. Supplementary Files 64CuSUPPLEMENTALrev.pdf Cite Share Download PDF Status: Published Journal Publication published 18 Jun, 2020 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 2 posted Editorial decision: Accept 25 May, 2020 Editor assigned by journal 24 May, 2020 Submission checks completed at journal 23 May, 2020 Editor invited by journal 23 May, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-23655","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":607785,"identity":"396df9df-ff36-4af3-9b7a-fbb6cff978e1","order_by":0,"name":"Kristoffer Kjærgaard","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACCQbGZiBhw8DHDBFgnEGkljQGNhK0MIDUHmZgYyBWi+Tsw80GFhXn5dnYeQ8w/GxjkJ3ZQECLNF9ic4LEmduGbcx8CYy9bQzGswnZIsfD2HxAsu12AhszjwEDbxtD4jzitPw7B9bC+JcYLdJALQmSDQfAWphBthB0mGQPY7OBxLFkoF94DA7LnJMwJuh9iTPsj6Ulauzk+fnPGD58U2YjO+MAIWuAgFkCyjgAjidiAOMH4tSNglEwCkbBSAUAjOszBKdqchkAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-6440-2784","institution":"Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital; Department of Hepatology and Gastroenterology, Aarhus University Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Kristoffer","middleName":"","lastName":"Kjærgaard","suffix":""},{"id":607786,"identity":"19e69c5c-d3e3-4838-bc36-adfa316aefe5","order_by":1,"name":"Thomas Damgaard Sandahl","email":"","orcid":"","institution":"Department of Hepatology and Gastroenterology, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"Damgaard","lastName":"Sandahl","suffix":""},{"id":607787,"identity":"b4bbca5a-d5cd-4cc7-8776-fc707ef263d0","order_by":2,"name":"Kim Frisch","email":"","orcid":"","institution":"Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kim","middleName":"","lastName":"Frisch","suffix":""},{"id":607788,"identity":"ee32b49e-fd3b-4588-ba08-ae649e5ade99","order_by":3,"name":"Karina Højrup Vase","email":"","orcid":"","institution":"Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Karina","middleName":"Højrup","lastName":"Vase","suffix":""},{"id":607789,"identity":"4f84c373-ac6b-413b-83f8-0da4871e867b","order_by":4,"name":"Susanne Keiding","email":"","orcid":"","institution":"Department of Hepatology and Gastroenterology, Aarhus University Hospital; Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Susanne","middleName":"","lastName":"Keiding","suffix":""},{"id":607790,"identity":"eda2f6c3-c142-4462-9331-99b153bc5526","order_by":5,"name":"Hendrik Vilstrup","email":"","orcid":"","institution":"Department of Hepatology and Gastroenterology, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hendrik","middleName":"","lastName":"Vilstrup","suffix":""},{"id":607791,"identity":"e0c8cc87-b9a2-4e0b-a042-94d4616de977","order_by":6,"name":"Peter Ott","email":"","orcid":"","institution":"Department of Hepatology and Gastroenterology, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Ott","suffix":""},{"id":607792,"identity":"3cb61cdc-13e0-4594-ac0b-260e75ec8f81","order_by":7,"name":"Lars Christian Gormsen","email":"","orcid":"","institution":"Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lars","middleName":"Christian","lastName":"Gormsen","suffix":""},{"id":607793,"identity":"bb97f7eb-1a7c-410a-a78b-a781f76fcc51","order_by":8,"name":"Ole Lajord Munk","email":"","orcid":"","institution":"Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ole","middleName":"Lajord","lastName":"Munk","suffix":""}],"badges":[],"createdAt":"2020-04-17 16:38:15","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-23655/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-23655/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41181-020-00100-1","type":"published","date":"2020-06-18T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":1222651,"identity":"d9e4e8fb-15f2-46db-88dd-c21f83356ea3","added_by":"auto","created_at":"2020-06-01 18:36:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":358177,"visible":true,"origin":"","legend":"Whole-body PET images (maximum intensity projection) showing the biodistribution of 64Cu after intravenous (upper panels) and oral (lower panels) administration in two healthy individuals (IV4 and O2)\nPET imaging was performed 1.5, 6, and 20 h after administration. Arrows identify most visible source organs.","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-23655/v2/1.jpg"},{"id":1222652,"identity":"5c8389eb-1110-4965-bede-cafbc909afd1","added_by":"auto","created_at":"2020-06-01 18:36:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1393322,"visible":true,"origin":"","legend":"Time courses of %AD in source organs following intravenous (IV) and oral administration of 64Cu\nUpper panels show the biodistribution of 64Cu after IV (a) and oral (b) administration. Lower panels show %AD in liver tissue during the initial dynamic PET/CT scan (c; 90 min) and including static whole-body PET scans from the entire study period (d; 20 h); closed circles show the time course after IV administration, open circles after oral administration. All values are given as group means ± SD.\n*Summation of small and large intestine.","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-23655/v2/2.jpg"},{"id":1222653,"identity":"86a18c0d-df38-4787-a3c1-6ef99677c68d","added_by":"auto","created_at":"2020-06-01 18:36:18","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":866040,"visible":true,"origin":"","legend":"Time courses of the concentration of 64Cu in blood following administration intravenous (IV) and oral administration\nPanel a shows SUV in arterial whole blood (closed circles) and plasma (open circles) following the initial 90 min after IV administration of 64Cu (n = 3; for clarity, no error bars are displayed); displayed as insert is the ratio between radioactivity concentration in whole blood and plasma. Panel b shows SUV in venous whole blood following IV and oral administration of 64Cu (n = 4 and n = 2, respectively). Values are given as group means ± SD.","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-23655/v2/3.jpg"},{"id":15667194,"identity":"8e3a79f3-3367-42cb-977d-bc8a376a73ed","added_by":"auto","created_at":"2021-11-18 13:40:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":609638,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-23655/v2/535370b9-a1ee-43f8-99ca-0546a36da98d.pdf"},{"id":1222654,"identity":"abd17f83-263b-4b1d-9e52-eb87766e6eac","added_by":"auto","created_at":"2020-06-01 18:36:18","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":328916,"visible":true,"origin":"","legend":"","description":"","filename":"64CuSUPPLEMENTALrev.pdf","url":"https://assets-eu.researchsquare.com/files/rs-23655/v2/64CuSUPPLEMENTALrev.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eIntravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [\u003csup\u003e64\u003c/sup\u003eCu]copper PET/CT\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCopper is an essential mineral present in all tissues and is important for several enzymatic processes [1]. It is absorbed in the upper intestine and taken up by the liver via the portal vein. From the liver, copper is either distributed to the systemic circulation bound to ceruloplasmin or, in the case of excess, excreted into the bile [2]. Disturbances in copper homeostasis are potentially fatal as seen in the rare genetic disorder of Wilson\u0026rsquo;s disease, where accumulation of toxic levels of copper in various organs leads to critical symptoms from the liver and central nervous system [3].\u003c/p\u003e\n\u003cp\u003eHuman copper metabolism and kinetics are only partly understood despite recent advances in molecular imaging, notably positron emission tomography (PET). [\u003csup\u003e64\u003c/sup\u003eCu]copper\u003ca href=\"#_ftn1\" name=\"_ftnref1\"\u003e[1]\u003c/a\u003e (\u003csup\u003e64\u003c/sup\u003eCu) PET is characterized by high spatial resolution (positron range, 0.7 mm in water), and the radioactive half-life of \u003csup\u003e64\u003c/sup\u003eCu (\u003cem\u003et\u003c/em\u003e\u003csub\u003e1/2\u003c/sub\u003e = 12.7 h) allows for \u003cem\u003ein vivo\u003c/em\u003e assessment of copper biodistribution, even in compartments with slow copper turnover [4]. To date, only few \u003csup\u003e64\u003c/sup\u003eCu PET studies of biodistribution and radiation dosimetry after intravenous injection in humans have been published, but it remains unclear which organs are the most critical in terms of radiation exposure [5-7]. In addition, no such studies have been published with oral administration of \u003csup\u003e64\u003c/sup\u003eCu, the natural entrance route of copper in humans.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e64\u003c/sup\u003eCu PET/CT has been used in the context of cancer detection and characterization [6-9], utilizing the overexpression of the human copper transporter 1 (CTR1) in malignant cells [10]. To our knowledge, no studies have yet examined the potential of \u003csup\u003e64\u003c/sup\u003eCu PET/CT to assess temporal whole-body copper homeostasis in humans, in particular hepatic copper uptake, accumulation and excretion.\u003c/p\u003e\n\u003cp\u003eIn this study, we determined the hepatic kinetics of \u003csup\u003e64\u003c/sup\u003eCu, characterized copper biodistribution and estimated the radiation dosimetry of \u003csup\u003e64\u003c/sup\u003eCu in healthy humans by sequential whole-body PET imaging spanning 1.5 to 20 h after intravenous as well as oral administration. The image based biodistribution estimates were supplemented by measurements of radioactive concentrations in blood, urine and faecal samples.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003ca href=\"#_ftnref1\" name=\"_ftn1\"\u003e[1]\u003c/a\u003e \u003cem\u003eIn vivo\u003c/em\u003e \u003csup\u003e64\u003c/sup\u003eCu-ions exist in different oxidation states and with various exchangeable counter-ions. Throughout this paper, these \u003csup\u003e64\u003c/sup\u003eCu-labelled species are referred to collectively as \u0026ldquo;\u003csup\u003e64\u003c/sup\u003eCu\u0026rdquo;.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003eRadiochemistry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCyclotron-produced \u003csup\u003e64\u003c/sup\u003eCu (nuclear reaction: \u003csup\u003e64\u003c/sup\u003eNi(p,n)\u003csup\u003e64\u003c/sup\u003eCu) was obtained from a commercial source (the Hevesy Laboratory, DTU Nutech, Ris\u0026oslash;, Roskilde, Denmark) and delivered to our centre as solid \u003csup\u003e64\u003c/sup\u003eCuCl\u003csub\u003e2\u003c/sub\u003e (radionuclidic purity \u0026ge; 99 %; specific activity \u0026ge; 1.0 TBq/\u0026micro;mol) on the day of the study (one batch production of \u003csup\u003e64\u003c/sup\u003eCuCl\u003csub\u003e2\u003c/sub\u003e was used over two days for two or three participants). Before use, the received \u003csup\u003e64\u003c/sup\u003eCuCl\u003csub\u003e2\u003c/sub\u003e was dissolved in sterile 0.1 M HCl (1 mL), pH was adjusted to around 5 with sterile 0.5 M sodium acetate buffer (0.5 mL), and sterile saline (8.5 mL) was added. The acetate buffered \u003csup\u003e64\u003c/sup\u003eCu solution was finally passed through a sterilizing filter (0.22 \u0026micro;m) into a sterile product vial. Quality control of the \u003csup\u003e64\u003c/sup\u003eCu solution consisted of pH measurement (pH strips; specification: 4-6), radiochemical purity test (radio-TLC; specification: \u0026ge;95%), LAL-test (PTS Endosafe, Charles River Laboratories; specification: \u0026lt;17.5 EU/ml), radionuclide identification (gamma spectrum; germanium detector; specification: 511 + 1346 keV), and sterile filter test (pressure-hold-test; specification: filter intact). The preparation and quality control of the \u003csup\u003e64\u003c/sup\u003eCu solution was approved by the Danish Medicines Agency.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design and Participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBiodistribution and dosimetry for \u003csup\u003e64\u003c/sup\u003eCu after intravenous and oral administration were determined by dynamic liver and subsequent whole body PET/CT in six healthy human participants (age 22-61 years). Four participants received intravenous administration (IV1-IV4; two males, two females) and two received oral administration (O1-O2; one male, one female) of \u003csup\u003e64\u003c/sup\u003eCu (Table 1). In an additional four participants (IV5-IV8; 2 males, two females) blood, urine, and faecal samples were collected after intravenous \u003csup\u003e64\u003c/sup\u003eCu administration, but without PET imaging (Supplemental Table 1). Participants fasted for at least 6 h before administration of \u003csup\u003e64\u003c/sup\u003eCu, but were allowed to drink water. Study inclusion criteria were: Age above 18 years, and for females, negative pregnancy test and use of safe contraception. Criteria for exclusion were known hypersensitivity to ingredients in the formula, use of drugs that affect copper metabolism, history of clinical disease, current pregnancy, breastfeeding, or desire to become pregnant. No complications to the procedures were observed.\u003c/p\u003e\n\u003ctable style=\"float: left;width:490.2pt;border-collapse:collapse;border:none;margin-left:4.8pt;margin-right:4.8pt;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99pt;border: 1pt solid windowtext;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height: normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Helvetica; font-size: 13px; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 260.8pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e\u003cstrong\u003eIV\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 130.4pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e\u003cstrong\u003eOral\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height: normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e\u003cem\u003eID\u003c/em\u003e (sex/age)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003eIV1 (M/61)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003eIV2 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0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e27.0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e24.4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height: normal;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e\u003cstrong\u003eEffective Dose\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e67.6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e56.2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n 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Helvetica;\"\u003e61.3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e114.0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65.2pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(191, 191, 191);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:normal;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e112.0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eParticipant characteristics, gender-averaged absorbed dose estimates (\u0026micro;Gy/MBq), and effective dose (\u0026micro;Sv/MBq) for \u003csup\u003e64\u003c/sup\u003eCu\u003csup\u003e\u0026nbsp;\u003c/sup\u003eby intravenous (IV) and oral administration\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003eData for critical target organs and effective doses for all individuals are displayed; for full list of organs, see Supplemental Table 3.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:.0001pt;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-size: 13px;\"\u003e\u003cspan style=\"font-family: Helvetica;\"\u003e*Dynamic PET/CT scan and blood samples not obtained.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style=\"font-family: Helvetica; font-size: 13px; color: rgb(0, 0, 0);\"\u003eAbbreviations: \u003cem\u003eBW\u003c/em\u003e = Body Weight; \u003cem\u003eRLI\u003c/em\u003e = Right Large Intestine; \u003cem\u003eLLI\u003c/em\u003e = Left Large Intestine.\u003c/span\u003e\u003c/p\u003e\u003cbr\u003e\n\u003cp\u003e\u003cstrong\u003ePET/CT Acquisition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participants were placed in supine position in a Siemens Biograph\u003csup\u003eTM\u003c/sup\u003e 64 TruePoint\u003csup\u003eTM\u003c/sup\u003e PET/CT camera within the 21.6 cm axial field-of-view. A low dose CT scan (50 effective mAs with CARE Dose4D, 120 kV, pitch of 0.8 mm, slice thickness 5.0 mm) was performed before each PET scan for definition of anatomic structures and attenuation correction of the PET images. The \u003csup\u003e64\u003c/sup\u003eCu solution was administered as an intravenous bolus injection (n = 4; median dose 73.5 MBq, range 66-116 MBq) or dissolved in water and swallowed (n = 2; median dose 65.5 MBq, range 57\u0026ndash;74 MBq). All participants underwent a dynamic PET scan of 90 min (dynamic PET and blood sampling were not acquired for one participant, see Table 1) with field-of-view over the liver, recorded in list-mode; time frame structure was 12x5 s, 8x15 s, 7x60 s, and 16x300 s. This was followed by three consecutive whole-body PET/CT scans (top of skull to mid-thigh; 6 bed positions) performed at 1.5, 6, and 20 h after tracer administration (duration 6, 6, and 10 min per bed position). The PET images were reconstructed using 3-dimensional ordered-subset expectation maximization with 4 iterations and 21 subsets, 4-mm Gauss filter, and 168x168 matrix with voxel size 4x4x5mm\u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage Processing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe fused PET/CT images were analysed using the PMOD 3.7 software (PMOD Technologies Ltd, Z\u0026uuml;rich, Switzerland). For kinetic analysis, the time course of the activity concentration of \u003csup\u003e64\u003c/sup\u003eCu during the 90-min dynamic PET scan was measured in a volume-of-interest (VOI) placed in the right liver lobe. The VOIs were drawn to contain liver tissue while avoiding large intrahepatic blood vessels and bile ducts. For biodistribution and dosimetry calculations, all tissues were visually inspected on images of the 1.5 h, 6 h, and 20 h whole body scans by two investigators. Organs with accumulation of \u003csup\u003e64\u003c/sup\u003eCu above that of surrounding tissue were defined as source organs: liver, gallbladder contents, small intestine, left large intestine (descending and sigmoid colon), right large intestine (ascending and transverse colon), rectum, stomach contents, kidneys, pancreas (IV only), and red bone marrow. VOIs were manually drawn for each source organ to encompass all radioactivity of the respective organ. The red bone marrow activity was estimated based on VOIs in the lumbar vertebrae as described by McParland [11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlood, Urine and Faecal Samples\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the intravenous study, arterial blood samples were collected from a radial artery during the initial dynamic PET scan at time points 12x5 s, 8x15 s, 7x60 s, and 16x300 s. In the oral study, venous blood samples were collected from a peripheral vein during the initial dynamic PET scan and before each of the consecutive whole-body scans (1.5 h, 6 h, and 20 h). In additional four participants with intravenous tracer administration (IV5-8), venous blood samples were obtained as for the oral study, and total urine and faeces were collected from 0-6 h and 6-20 h. Radioactivity concentrations of \u003csup\u003e64\u003c/sup\u003eCu were measured in whole blood, plasma, urine, and faeces using a well gamma counter (Packard 5003, Packard Instruments, USA). Time courses of the activity concentration in blood and plasma were generated for 90 min with two additional samples at 6 h and 20 h. Total output in percent of administered dose (%AD) for urine and faeces were calculated for time points 6 h and 20 h. All concentration measurements were cross-calibrated with the PET-camera and corrected for radioactive decay back to start of the tracer administration. Prior to the injection of radiotracer, a venous blood sample was drawn for measurement of baseline blood tests of liver and kidney function, haematological quantities, and copper metabolism.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eModelling of Hepatic Kinetics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKinetic parameters were estimated by fitting kinetic models to the dynamic liver PET data using the time course of arterial plasma \u003csup\u003e64\u003c/sup\u003eCu as input function. To account for the hepatic dual blood supply from the hepatic artery (25%) and portal vein (75%), we used reversible linearised models that allow robust and unbiased estimates using only the arterial input function [12]. Two kinetic models were used: 1) The Gjedde-Patlak linearisation yielding the steady-state clearance from blood to liver tissue (\u003cem\u003eK\u003c/em\u003e; mL blood/min/mL liver tissue) including a small reversible loss rate constant (\u003cem\u003ek\u003c/em\u003e\u003csub\u003eloss\u003c/sub\u003e; min\u003csup\u003e-1\u003c/sup\u003e), representing the loss of tracer from the liver hepatocytes into bile or blood [13]; 2) the Logan linearisation [14] that estimates the total distribution volume (\u003cem\u003eV\u003c/em\u003e\u003csub\u003ed\u003c/sub\u003e; mL blood/mL liver tissue) of \u003csup\u003e64\u003c/sup\u003eCu in the liver. Both kinetic models were applied to data 30 to 90 min after tracer administration to ensure quasi-steady-state. The kinetic model parameters were estimated using software developed in-house (Supplemental Figure 1).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiodistribution and Dosimetry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor each source organ, the time course of the non-decay-corrected total radioactivity was normalised to the administered activity and recalculated to time courses of percentage injected activity. Time-integrated activity coefficients (TIACs) were computed using the trapezoidal integration method to calculate the area under the curves, assuming only physical decay after the last scan without further biological clearance. The remainder TIAC was calculated by subtracting the individual source organ TIACs from the total body TIAC (without voiding), which for \u003csup\u003e64\u003c/sup\u003eCu is 18.3 h. TIACs for source organs and remainder were used in OLINDA/EXM 2.0 (HERMES Medical Solution AB, Sweden) [15] to compute organ absorbed doses (\u0026mu;Gy/MBq) and the effective dose (\u0026mu;Sv/MBq) using anthropomorphic human body phantoms with organ masses based on ICRP89 [16] and ICRP103 tissue weighting factors [17]. Organ doses and effective dose results are given for the reference gender-averaged adult according to ICRP103.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBiodistribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigures 1 and 2A-B show whole-body PET/CT and time-activity curves for the biodistribution of \u003csup\u003e64\u003c/sup\u003eCu. \u003csup\u003e64\u003c/sup\u003eCu was avidly taken up by the liver after both intravenous and oral administration with the highest concentrations reached after 6 h, where %AD in the liver was 47 \u0026plusmn; 1.35 % and 34 \u0026plusmn; 0.01 % (mean \u0026plusmn; SD), respectively. In addition, radioactivity was observed in the red bone marrow and kidneys. Uniquely for the intravenous administration, \u003csup\u003e64\u003c/sup\u003eCu was taken up by the pancreas, intestinal walls, and salivary glands (Figure 1). After oral administration, the biodistribution of \u003csup\u003e64\u003c/sup\u003eCu was dominated by efficient uptake by the liver and varying degrees of residual activity in the intestinal lumen. Approximately 1.5 h after administration for both groups, the variation in biodistribution between the participants was insignificant (Figure 2A-B). Accumulation of \u003csup\u003e64\u003c/sup\u003eCu in other organs, including the brain, urinary bladder, and prostate was negligible.\u003c/p\u003e\n\u003cp\u003eThe hepatic uptake of \u003csup\u003e64\u003c/sup\u003eCu was rapid after intravenous administration, whereas the uptake following oral administration was delayed (approximately 12 min) by the process of intestinal absorption (Figure 2C-D). Apart from the delay, the rate of uptake in liver tissue was comparable between the two administration forms with %AD in the liver peaking at 6 h followed by a minor decrease, most likely caused by biliary excretion and redistribution of \u003csup\u003e64\u003c/sup\u003eCu back to blood. The gallbladder was visible on the PET images in five of the six participants after 1.5 h, indicating some degree of biliary excretion at this time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHepatic Removal Kinetics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis of the hepatic removal kinetics of \u003csup\u003e64\u003c/sup\u003eCu following intravenous administration provided robust linear model-fits to the liver PET data (examples in Supplemental Figure 1). The steady-state hepatic clearance of \u003csup\u003e64\u003c/sup\u003eCu from blood into liver tissue (\u003cem\u003eK\u003c/em\u003e) was 0.10 \u0026plusmn; 0.02 mL blood/min/mL liver tissue with marginal loss of tracer into bile or blood (\u003cem\u003ek\u003c/em\u003e\u003csub\u003eloss\u003c/sub\u003e = 0.003 \u0026plusmn; 0.002 min\u003csup\u003e-1\u003c/sup\u003e); the hepatic volume of distribution (\u003cem\u003eV\u003c/em\u003e\u003csub\u003ed\u003c/sub\u003e) was 36 \u0026plusmn; 22 mL blood/mL liver tissue (mean \u0026plusmn; SD; n = 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlood, Urine and Faeces\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter intravenous administration, arterial \u003csup\u003e64\u003c/sup\u003eCu was rapidly cleared from the systemic circulation; the whole-blood to plasma activity ratio was approximately 55%, increasing slowly during the initial 90 min (Figure 3A). The venous \u003csup\u003e64\u003c/sup\u003eCu showed a similar pattern and increased slowly for the remaining study period (Figure 3B). After oral administration, venous blood concentrations increased until approximately 1 hour and then gradually subsided before a late slow increase, comparable to that observed after intravenous administration (Figure 3B). The low radioactivity concentration in venous blood following oral administration illustrates the efficient first-pass extraction of \u003csup\u003e64\u003c/sup\u003eCu through the liver.\u003c/p\u003e\n\u003cp\u003eAfter intravenous administration, insignificant amounts of \u003csup\u003e64\u003c/sup\u003eCu were measured in urine (mean %AD \u0026plusmn; SD: 0.0013 \u0026plusmn; 0.0006) and faeces (median %AD [range]: 0.0022 [0.0002-0.0416]) during the study period (Supplemental Figure 2). Urine and faeces were not collected after oral administration. Baseline blood tests were all within normal range or near-normal (Supplemental Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiation Dosimetry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipant characteristics and dosimetry data are given in Table 1; the full list of organs is given in Supplemental Table 3. After intravenous administration, the most critical organ was the liver (range 415-467 \u0026micro;Gy/MBq), followed by the small intestines (range 168-238 \u0026micro;Gy/MBq). After oral administration, the most critical organ was the right large intestine (range 600-925 \u0026micro;Gy/MBq), followed by the small intestines (range 369-378 \u0026micro;Gy/MBq), liver (range 317-335 \u0026micro;Gy/MBq), and stomach (range 238-274 \u0026micro;Gy/MBq). Importantly, the radiation exposure to the intestines was highly dependent on individual peristalsis and intestinal transit time as observed in participant O1, where the right large intestine received as much as 925 \u0026micro;Gy/MBq and the left large intestine, almost nothing. In contrast, the radiation dose to the liver varied very little between the participants for both administration forms. The gender-averaged effective doses after intravenous and oral administration were 62 \u0026plusmn; 5 and 113 \u0026plusmn; 2 \u0026micro;Sv/MBq (mean \u0026plusmn; SD).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we report \u003csup\u003e64\u003c/sup\u003eCu PET/CT results on biodistribution, dosimetry, and hepatic removal kinetics following both intravenous and oral administration of the radiotracer in healthy humans.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003e64\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003eCu Biodistribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing absorption in the intestines, copper is transported into the portal blood circulation by the ATP7A transporter located in the basolateral membrane of the enterocytes [18]. In the portal vein, copper is bound to albumin, in particular, and to other plasma proteins in a highly exchangeable pool [19, 20]. Albumin-bound copper in systemic plasma has a half-life of 10-20 min [21] and is effectively extracted during the hepatic first pass (\u0026gt;80%) [22]. In the present study, uptake of \u003csup\u003e64\u003c/sup\u003eCu from the systemic circulation after intravenous administration was observed in tissues characterised by high expression of the CTR1 transporter such as the liver, pancreas, intestinal walls, and kidneys [23]. After intravenous administration, \u003csup\u003e64\u003c/sup\u003eCu was not excreted in urine and only a negligible amount was detected in faeces during the 20-hour observation period.\u003c/p\u003e\n\u003cp\u003eAfter oral administration, the biodistribution was dominated by the hepatic first pass extraction of \u003csup\u003e64\u003c/sup\u003eCu, whereas uptake in organs other than the liver, kidneys, and red bone marrow was negligible when compared with intravenous administration. Moreover, the total %AD taken up from the intestines and measured in source organs did not exceed 50%, which is in accordance with net intestinal copper absorption studies in pigs and humans [20, 24]. It should be noted that the intestinal absorption of copper is affected by the dietary composition and our results therefore only reflect conditions in the 6 h fasting state [25].\u003c/p\u003e\n\u003cp\u003eIn the liver, copper is incorporated in ceruloplasmin (biological half-life: 13 hours) and then redistributed into the systemic circulation 2-3 days after administration, creating a second peak in blood concentration, also known as the ceruloplasmin wave [26, 27]. In the present study, the blood concentration of \u003csup\u003e64\u003c/sup\u003eCu steadily increased after the peak following administration, reflecting copper incorporation into ceruloplasmin. The arterial blood to plasma radioactivity ratio was approximately 55% and increased over the first 90 min, possibly reflecting copper uptake in erythrocytes by the anion exchanger located in the erythrocyte membrane [28].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003csup\u003e64\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003eCu Dosimetry\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDosimetry estimates for intravenous administration of \u003csup\u003e64\u003c/sup\u003eCu showed that the liver was the most critical organ, followed by the small intestines. Reports of dosimetry estimates for intravenous administration of \u003csup\u003e64\u003c/sup\u003eCu differ to some extent. In the present study, radiation exposure to the liver and intestines was considerably higher and the effective dose twice of that previously reported in patients with prostate cancer [6, 7]. This difference is likely because of different analytical approaches rather than altered biodistribution of \u003csup\u003e64\u003c/sup\u003eCu in patients with prostate cancer compared with healthy subjects. However, our results, based on the newest phantoms and tissue weighing factors [15-17], are in agreement with the observations made by Avila-Rodriguez et al. in healthy participants [5].\u003c/p\u003e\n\u003cp\u003eTo our knowledge, dosimetry estimates for oral administration of \u003csup\u003e64\u003c/sup\u003eCu have not previously been reported. As expected, the radiation dosimetry of \u003csup\u003e64\u003c/sup\u003eCu after oral and intravenous administration differed significantly. While the liver was exposed to a high radiation dose after oral administration, equal or higher doses were received by the intestines due to high amounts of unabsorbed radiotracer. In this context, it is important to acknowledge that the radiation dose to the intestines depends on the individual intestinal transit time, unlike for intravenous administration; in our study, one participant received 925 \u0026micro;Gy/MBq to the right large intestine. Consequently, the radiation dosimetry of \u003csup\u003e64\u003c/sup\u003eCu by oral administration may differ substantially between individuals, necessitating a cautious approach to total oral dose used in future studies. Based on our results, the total radiation dose received by the reference gender-averaged adult after an oral ingestion of 50 MBq \u003csup\u003e64\u003c/sup\u003eCu amounts to 5.6 mSv, ensuring less than 50 mSv absorbed by a single organ. This dose is sufficient to obtain high-quality PET images, and may still be reduced by at least 50% with new digital PET systems yielding faster time-of-flight timing resolution and higher NEMA sensitivity. Thus, \u003csup\u003e64\u003c/sup\u003eCu PET using intravenous or oral administration is suitable for studying copper metabolism in humans. In this context, it is worth noting that because of the commercial availability and long half-life of the \u003csup\u003e64\u003c/sup\u003eCu radioisotope, \u003csup\u003e64\u003c/sup\u003eCu PET can be performed also at PET centres without the necessary facilities to produce \u003csup\u003e64\u003c/sup\u003eCu.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCopper Metabolism\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe use of radioactive Cu isotopes to assess copper metabolism in humans was introduced decades ago, and many studies on this topic have been published since then [29-32]. Most recently, Czlonkowska et al. showed that measurements of \u003csup\u003e64\u003c/sup\u003eCu in blood and in urine following intravenous injection accurately distinguished between patients with Wilson\u0026rsquo;s disease and heterozygote controls [32]. The obvious advantage of \u003csup\u003e64\u003c/sup\u003eCu-copper PET/CT is however, the potential for assessing also the hepatic uptake, accumulation, and turnover; this includes oral administration where the biodistribution is dominated by first pass extraction by the liver, as demonstrated in the present study. In addition, the PET/CT data on the accumulation of protein-bound \u003csup\u003e64\u003c/sup\u003eCu reported in this study provides valuable knowledge to help interpret unwanted copper loss in relation to the increasing research on \u003csup\u003e64\u003c/sup\u003eCu radiopharmaceuticals [33].\u003c/p\u003e\n\u003cp\u003ePeng et al. assessed hepatic copper kinetics in rats using \u003csup\u003e64\u003c/sup\u003eCu PET/CT [34], revealing some noteworthy differences between rodents and our human participants. For example, cardiac uptake of \u003csup\u003e64\u003c/sup\u003eCu was substantial in rodents whereas it was negligible in our human participants. Results from rodent copper studies can therefore not be easily translated to human conditions. In the present study, we were able to quantify the hepatic removal kinetics of \u003csup\u003e64\u003c/sup\u003eCu using dynamic PET/CT with measurements of arterial \u003csup\u003e64\u003c/sup\u003eCu concentration. The hepatobiliary excretion of \u003csup\u003e64\u003c/sup\u003eCu is slower than e.g. bile acids [35], but importantly, the properties of the \u003csup\u003e64\u003c/sup\u003eCu isotope allow for long-term studies of copper metabolism in humans.\u003c/p\u003e\n\u003cp\u003eOne of the primary therapeutic strategies in the treatment of Wilson\u0026rsquo;s disease is to inhibit absorption of dietary copper in order to reduce systemic and hepatic accumulation [3]. Because of the dominant hepatic first-pass extraction of copper following ingestion, the concentration of Cu in systemic blood may not be a reliable measure when assessing how well pharmaceuticals impair absorption of copper in the intestine. While intravenous administration of \u003csup\u003e64\u003c/sup\u003eCu bypasses this first-pass metabolism, \u003csup\u003e64\u003c/sup\u003eCu PET following oral administration proves useful for assessing the enterohepatic transport of copper \u003cem\u003ein vivo\u003c/em\u003e. Moreover, since oral ingestion of \u003csup\u003e64\u003c/sup\u003eCu reduces the invasiveness of the procedure, \u003csup\u003e64\u003c/sup\u003eCu PET/CT with oral administration would be more suitable for clinical evaluation of copper metabolism in patients with Wilson\u0026rsquo;s disease.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFor intravenous administration, the gender-averaged effective dose was 62 \u0026plusmn; 5 \u0026micro;Sv/MBq with the liver being the most critical organ. For oral administration, residual radiotracer in the gastrointestinal tract resulted in high radiation doses to the intestines, leading to an effective dose of 113 \u0026plusmn; 1 \u0026micro;Sv/MBq. We found that both intravenous and oral administrations of 50 MBq \u003csup\u003e64\u003c/sup\u003eCu were sufficient for sequential studies in humans, yielding images of high quality up to 20 hours after administration with radiation doses of approximately 3.1 mSv and 5.7 mSv, respectively. Thus, \u003csup\u003e64\u003c/sup\u003eCu PET/CT using intravenous and oral administration represent suitable methods for assessment of copper metabolism in humans, including the intestinal absorption, hepatic removal kinetics, and subsequent redistribution of copper.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements: \u003c/strong\u003eThe authors would like to thank the participants for enrolling in this study as well as the staff from the Department of Nuclear Medicine and PET-Centre, Aarhus University Hospital, for experimental assistance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions: \u003c/strong\u003e\u003cem\u003eTS\u003c/em\u003e, \u003cem\u003eSK\u003c/em\u003e, \u003cem\u003eHV\u003c/em\u003e, \u003cem\u003ePO\u003c/em\u003e, \u003cem\u003eLG\u003c/em\u003e and \u003cem\u003eOLM\u003c/em\u003e conceived the study. \u003cem\u003eTS\u003c/em\u003e, \u003cem\u003eSK\u003c/em\u003e and \u003cem\u003eLG\u003c/em\u003e performed the experimental procedures and \u003cem\u003eKF \u003c/em\u003eand \u003cem\u003eKV\u003c/em\u003e were in charge of the radiochemistry. \u003cem\u003eKK\u003c/em\u003e analysed data, performed statistical analyses and wrote the first draft of the manuscript together with \u003cem\u003eTS\u003c/em\u003e, \u003cem\u003eLG\u003c/em\u003e and \u003cem\u003eOLM\u003c/em\u003e. All authors contributed to, read, and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards: \u003c/strong\u003eThe study was approved by the Danish Medicines Agency (EudraCT no. 2016-001975-59) and the Central Denmark Region Committees on Health Research Ethics, conducted in accordance with the Helsinki II Declaration, and monitored by the Good Clinical Practice Unit (Aarhus University).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding: \u003c/em\u003eThis study was supported by an unrestricted research grant from the Foundation of Manufacturer Vilhelm Pedersen and Wife.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConflicts of interest: \u003c/em\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication:\u003c/em\u003e All participants signed written informed consent for participation in the study and regarding publication of their data and images.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and material:\u003c/em\u003e The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTapiero H, Townsend DM, Tew KD. 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The American journal of physiology. 1972;222:106-10. doi:10.1152/ajplegacy.1972.222.1.106.\u003c/li\u003e\n\u003cli\u003eAlda JO, Garay R. Chloride (or bicarbonate)-dependent copper uptake through the anion exchanger in human red blood cells. The American journal of physiology. 1990;259:C570-6. doi:10.1152/ajpcell.1990.259.4.C570.\u003c/li\u003e\n\u003cli\u003eSternlieb I, Scheinberg IH. Radiocopper in diagnosing liver disease. Seminars in nuclear medicine. 1972;2:176-88.\u003c/li\u003e\n\u003cli\u003eGunther K, Lossner V, Lossner J, Biesold D. The kinetics of copper uptake by the liver in Wilson's disease studied by a whole-body counter and a double labelling technique. European neurology. 1975;13:385-94. doi:10.1159/000114694.\u003c/li\u003e\n\u003cli\u003eHarvey LJ, Dainty JR, Hollands WJ, Bull VJ, Beattie JH, Venelinov TI, et al. Use of mathematical modeling to study copper metabolism in humans. The American journal of clinical nutrition. 2005;81:807-13. doi:10.1093/ajcn/81.4.807.\u003c/li\u003e\n\u003cli\u003eCzlonkowska A, Rodo M, Wierzchowska-Ciok A, Smolinski L, Litwin T. Accuracy of the radioactive copper incorporation test in the diagnosis of Wilson disease. Liver international : official journal of the International Association for the Study of the Liver. 2018;38:1860-6. doi:10.1111/liv.13715.\u003c/li\u003e\n\u003cli\u003eZhou Y, Li J, Xu X, Zhao M, Zhang B, Deng S, et al. (64)Cu-based Radiopharmaceuticals in Molecular Imaging. Technol Cancer Res Treat. 2019;18:1533033819830758. doi:10.1177/1533033819830758.\u003c/li\u003e\n\u003cli\u003ePeng F, Lutsenko S, Sun X, Muzik O. Imaging copper metabolism imbalance in Atp7b (-/-) knockout mouse model of Wilson's disease with PET-CT and orally administered 64CuCl2. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging. 2012;14:600-7. doi:10.1007/s11307-011-0532-0.\u003c/li\u003e\n\u003cli\u003e\u0026Oslash;rntoft NW, Munk OL, Frisch K, Ott P, Keiding S, S\u0026oslash;rensen M. Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography. Journal of hepatology. 2017;67:321-7. doi:10.1016/j.jhep.2017.02.023.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"64Cu, copper, kinetics, dosimetry, biodistribution","lastPublishedDoi":"10.21203/rs.3.rs-23655/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-23655/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eCopper is essential for enzymatic processes throughout the body. [\u003csup\u003e64\u003c/sup\u003eCu]copper (\u003csup\u003e64\u003c/sup\u003eCu) positron emission tomography (PET) has been investigated as a diagnostic tool for certain malignancies, but has not yet been used to study copper homeostasis in humans. In this study, we determined the hepatic removal kinetics, biodistribution and radiation dosimetry of \u003csup\u003e64\u003c/sup\u003eCu in healthy humans by both intravenous and oral administration. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eSix healthy participants underwent PET/CT studies with intravenous or oral administration of \u003csup\u003e64\u003c/sup\u003eCu. A 90 min dynamic PET/CT scan of the liver was followed by three whole-body PET/CT scans at 1.5, 6, and 20 h after tracer administration. PET data were used for estimation of hepatic kinetics, biodistribution, effective doses, and absorbed doses for critical organs. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAfter intravenous administration,\u003cstrong\u003e \u003c/strong\u003e\u003csup\u003e64\u003c/sup\u003eCu uptake was highest in the liver, intestinal walls and pancreas; the gender-averaged effective dose was 62 ± 5 μSv/MBq (mean ± SD). After oral administration, \u003csup\u003e64\u003c/sup\u003eCu\u003csub\u003e \u003c/sub\u003ewas almost exclusively taken up by the liver while leaving a significant amount of radiotracer in the gastrointestinal lumen, resulting in an effective dose of 113 ± 1 μSv/MBq. Excretion of \u003csup\u003e64\u003c/sup\u003eCu in urine and faeces after intravenous administration was negligible. Hepatic removal kinetics showed that the clearance of \u003csup\u003e64\u003c/sup\u003eCu from blood was 0.10 ± 0.02 mL blood/min/mL liver tissue, and the rate constant for excretion into bile or blood was 0.003 ± 0.002 min\u003csup\u003e-1\u003c/sup\u003e. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003e\u003csup\u003e64\u003c/sup\u003eCu biodistribution and radiation dosimetry are influenced by the manner of tracer administration with high uptake by the liver, intestinal walls, and pancreas after intravenous administration, and after oral administration, \u003csup\u003e64\u003c/sup\u003eCu is rapidly absorbed from the gastrointestinal tract and deposited primarily in the liver. Administration of 50 MBq \u003csup\u003e64\u003c/sup\u003eCu\u003csub\u003e \u003c/sub\u003eyielded images of high quality for both administration forms with radiation doses approximately 3.1 and 5.7 mSv, respectively, allowing for sequential studies in humans.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial Registration Number: \u003c/strong\u003eEudraCT no. 2016-001975-59. Registration date: 19/09/2016.\u003c/p\u003e","manuscriptTitle":"Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-06-01 18:36:17","doi":"10.21203/rs.3.rs-23655/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-05-25T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-05-24T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-05-23T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-05-23T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-04-22 21:15:16","doi":"10.21203/rs.3.rs-23655/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-05-06T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-05-05T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-04-28T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-04-25T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorAssigned","content":"","date":"2020-04-23T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-04-23T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-04-23T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvited","content":"","date":"2020-04-22T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-04-17T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-04-17T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cf6ea9b2-a524-48c5-89de-294d3d2f062c","owner":[],"postedDate":"June 1st, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":111041,"name":"Nuclear Medicine \u0026 Medical Imaging"}],"tags":[],"updatedAt":"2020-06-21T15:01:44+00:00","versionOfRecord":{"articleIdentity":"rs-23655","link":"https://doi.org/10.1186/s41181-020-00100-1","journal":{"identity":"ejnmmi-radiopharmacy-and-chemistry","isVorOnly":false,"title":"EJNMMI Radiopharmacy and Chemistry"},"publishedOn":"2020-06-18 12:00:00","publishedOnDateReadable":"June 18th, 2020"},"versionCreatedAt":"2020-06-01 18:36:17","video":"","vorDoi":"10.1186/s41181-020-00100-1","vorDoiUrl":"https://doi.org/10.1186/s41181-020-00100-1","workflowStages":[]},"version":"v2","identity":"rs-23655","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-23655","identity":"rs-23655","version":["v2"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}