Dosimetry and immunohistochemistry study to establish radiolabelled prostate-specific membrane antigen (PSMA) as a potential theranostic target in high-grade glioma treatment

Dosimetry and immunohistochemistry study to establish radiolabelled prostate-specific membrane antigen (PSMA) as a potential theranostic target in high-grade glioma treatment | 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 Dosimetry and immunohistochemistry study to establish radiolabelled prostate-specific membrane antigen (PSMA) as a potential theranostic target in high-grade glioma treatment Matthew Benger, Georgios Krokos, Karan Daga, Alan Wright, Istvan Bodi, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8603380/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Prostate-specific membrane antigen (PSMA) is upregulated in high-grade glioma (HGG). This study aimed, firstly, to establish dosimetry for the radionuclide [68Ga]-PSMA-11 in HGG patients; secondly, to determine theoretical tumour doses for [177Lu]-PSMA, a potential therapeutic radionuclide; thirdly, to assess PSMA immunohistochemistry in targeted intra-operative HGG biopsies. Three HGG patients underwent PET-MRI after injection of 185 MBq [68Ga]-PSMA-11. Targeted intra-operative HGG biopsies were immunostained for PSMA and endothelium (CD34). There was durable, heterogeneous uptake of [ 68Ga]-PSMA-11 with moderate SUVmax (4.2-5.0) and high TBR (60-183). [68Ga]-PSMA-11 delivered a tumour dose of 0.01-0.03 mGy/MBq corresponding to 0.38-1.10 mGy/MBq for [177Lu]-PSMA. PSMA staining was predominantly seen in necrotic/proliferating CD34-positive cells. HGGs exhibited moderate and heterogeneous [68Ga]-PSMA-11 uptake, corresponding to a theoretical [177Lu] tumour dose lower than conventional external beam radiotherapy but within the range used for theranostic treatment in prostate cancer. PSMA staining was most prevalent in regions of tumour with necrotic/proliferating endothelium. Theranostic High-Grade Glioma (HGG) PSMA PET-MRI Figures Figure 1 Figure 2 Figure 3 Introduction High-grade glioma (HGG) is incurable with a life expectancy of under two years[ 1 ]. ‘Theranostic’ radiotherapy uses a targeted radionuclide to confirm the presence, concentration and distribution of a target protein (using a gamma or positron emitter) as a condition for targeted radionuclide therapy (using an alpha or beta emitting analogue). This strategy has shown safety and efficacy in metastatic prostate cancer by targeting prostate-specific membrane antigen (PSMA)[ 2 ]. Importantly, PSMA has been reported to be upregulated in HGG[ 3 ]. Following single case studies[ 4 , 5 ], a recent multi-centre study demonstrated specific uptake of a PSMA-targeted radionuclide, [ 68 Ga]-PSMA-11, in HGG using PET-MRI and endothelial expression of PSMA in targeted brain biopsies[ 6 ]. We prospectively investigated the use of [ 68 Ga]-PSMA-11 in UK HGG patients to add to the limited global evidence. Specific objectives were to establish dosimetry; calculate theoretical deliverable tumour doses for a potential therapeutic radionuclide; and assess PSMA immunohistochemistry in targeted intra-operative HGG biopsies. Methods Patients Three HGG patients were enrolled consecutively in a prospective study at King’s College NHS Foundation Trust, UK. All three patients had a new presumed HGG diagnosis based on clinical and imaging findings and had not undergone any prior treatment. PET-MR scanning In the interval between receiving a diagnosis of likely HGG and surgery, patients underwent a 75 min dynamic PET-MRI study with injection of 174–188 MBq [ 68 Ga]-PSMA-11 (t = 0) on a Biograph mMR scanner (Siemens Healthineers, Erlangen, Germany) followed by a 10, 20 and 40 min static scan at 120, 180 and 240 min post-injection (Supplementary Data). Imaging acquisition and postprocessing are detailed in the Supplementary Data. PET-MR Image Analysis Standardised Uptake Values (SUV) were calculated from regions of interest (ROI) and semi-quantitative analysis of tumour uptake derived. TBR max was calculated by dividing SUV max of tumour by SUV mean of the corresponding contralateral region of brain parenchyma. The target-to-off target ratio was calculated by dividing tumour SUV max by the mean SUV mean from the left and right parotid glands using a 10 mm diameter sphere placed at their centre. All quantitative image analysis was performed on MIM version 7.0 (MIM Software Inc., Beachwood, USA). To assess any differences in the distribution of post-gadolinium enhancement and PSMA uptake in the tumours, the overlap of contrast enhancement on T 1 + c and tracer uptake on the co-registered PET study was assessed by two neuroradiologists (UK Fellow (US Fellow equivalent); 5-years neuroimaging experience. UK Consultant (US Attending equivalent); 20-years neuroimaging experience). Dosimetry Motion correction was performed by rigidly registering the dynamic and late static PET images to the PET 60 − 75 reconstruction. Regions of the whole-tumour, necrotic core, enhancing rim, and salivary/lacrimal glands were delineated using the co-registered PET 60 − 75 and T 1 + c image. Time-activity curves (TACs) from 0-240 min were generated for each ROI. Physical decay was assumed from 240 min post-injection and the time-integrated activity coefficients (TIACs) were estimated using the trapezoidal method having expressed TACs to values of proportion of injected dose (%ID). TACs were decay-corrected to the point of injection and recalculated using the t½ of [ 177 Lu] (6.643 days) to estimate TIACs as performed by Peters et al [ 7 ]. Tracer uptake beyond 240 min was assumed at equilibrium and only the physical decay of the isotope was further considered in dosimetry calculations. Olinda 1.1 (Hermes, Stockholm, Sweden) was used to estimate tumour and salivary gland doses. Immunohistochemistry Three patients underwent two, three and five brain tumour biopsies respectively using intra-operative neuronavigation (StealthStationTM S8 Navigation Platform, Medtronic, Minneapolis, USA), targeting regions of tumour with varying PET tracer uptake. The number of biopsies performed were determined preoperatively according to safety criteria for tissue sampling. Samples were formalin-fixed and immunostained with mouse anti-PSMA (3E6, Agilent Technologies, Santa Clara, USA) and mouse anti-CD34 antibodies (QBEnd/10, Ventana Medical Systems, Tucson, USA). Sections were analysed by a neuropathologist (UK Consultant (US Attending equivalent); 15 years neuropathology experience) with endothelial intensity quantified using a 5-point visual Likert scale (0 – none, 1 – mild, 2 – moderate, 3 – high, 4 – very high). Statistical analysis was performed using GraphPad Prism (Version 10.3.1). A P value of < 0.05 was set to determine statistical significance. Results Uptake of PSMA in tumour In all three patients, tumour %ID and SUV mean increased up to ~ 70 min then remained constant up to 240 min (Fig. 1 ). [ 68 Ga]-PSMA-11 demonstrated heterogeneous uptake in solid tumour with no uptake within cavities (Fig. 2 ). Regions of increased PSMA uptake generally enhanced on T 1 + c. Interestingly, in one patient there was a region of high uptake with only faint gadolinium enhancement (Fig. 2 ). rCBV mildly increased within enhancing tumour for patients 1 and 3, without clear overlap with high SUV regions. Although there are insufficient data for quantitative correlation between tracer uptake and K trans /V e parameters, regions of high K trans and V e appeared to show high tracer uptake (Fig. 2 ). Overall, there was a moderate tumour SUV max (4.20 − 10.95) and SUV mean (1.44–4.43), and a high TBR max (60–183) (Table 1 ). Off-target uptake in the salivary/lacrimal glands and retropharyngeal tissue ranged from 0.026–0.075 mGy/MBq (Table 2 ), corresponding to a dose range of 0.85–2.59 mGy/MBq when extrapolated to equivalent [ 177 Lu]-PSMA-11 (Table 2 ). Table 1 Patient age/sex, histopathological diagnosis (using the 2021 WHO brain tumour classification), tumour volume, SUV max , SUV mean , TBR max and target to off-target ratio as estimated from PET 60 − 75 Age (years)/Sex (M/F) Histopathology Diagnosis Tumour volume (ml) Tumour SUV max Tumour SUV mean TBR max Target to off-target ratio Patient 1 63/M Glioblastoma IDH WT 35 4.20 1.44 60 0.40 Patient 2 37/M Diffuse paediatric-type HGG, H3 WT, IDH WT 35 5.04 1.85 84 0.46 Patient 3 53/M Glioblastoma IDH WT 45 10.95 4.43 183 0.90 Abbreviations: SUV = Standardised Uptake Value; TBR = tumour-to-background ratio; HGG = High-Grade Glioma; IDH = Isocitrate Dehydrogenase; WT = Wild Type; H3 = histone H3. Table 2 Dose range to on-target and off-target tissues after [68Ga]-PSMA-11 injection as estimated from PET60-75 and extrapolated for [177Lu]-PSMA-11. Region Dose for [ 68 Ga]-PSMA-11 (mGy/MBq) Dose for [ 177 Lu]-PSMA-11 (mGy/MBq) Enhancing Tumour 0.011–0.030 0.38–1.10 Parotid glands 0.050–0.062 1.83–2.22 Sublingual glands 0.026–0.037 0.85–1.19 Submandibular glands 0.046–0.075 1.73–2.44 Lacrimal glands 0.028–0.067 1.26–2.59 Tonsillar and Retropharyngeal tissue 0.025–0.034 0.66–1.01 PSMA immunohistochemistry In all three patients, there was significant variation in PSMA staining, which was strongest and most consistent in necrotic/proliferating tumour endothelium (Fig. 3 ). Conversely, several sections demonstrated only mild staining with numerous negative regions of endothelium. Variable PSMA positivity was seen in non-endothelial regions and considered likely to represent reactive cells. The intensity of PSMA immunostaining within solid regions of tumour was correlated to [ 68 Ga]-PSMA-11 uptake, revealing only a weakly positive correlation (Pearson correlation coefficient r = 0.27, p = 0.45) (Supplementary Data). Discussion This study demonstrated durable but heterogeneous uptake of a PSMA-directed radionuclide in HGG with a moderately high SUV max and a high TBR, consistent with prior studies[ 5 , 6 , 8 ]. Tumour gadolinium enhancement and tracer uptake broadly overlapped. Notably, this is the first study to also demonstrate a region of notable mismatch between [ 68 Ga]-PSMA uptake and gadolinium enhancement. While faint gadolinium enhancement in this region implies early blood brain barrier breakdown and may at least partly explain increased [ 68 Ga]-PSMA permeability and retention, the degree of uptake raises the possibility that PSMA PET-MRI could provide complementary information to T 1 + c sequences in identifying regions of higher-grade tumour. The qualitative overlap between regions of high tracer uptake and high capillary permeability, together with strong PSMA staining within necrotic/proliferating tumour endothelium (a recognised hallmark of HGG[ 9 ]), supports the notion that [ 68 Ga]-PSMA-11 primarily targets areas of tumour neoangiogenesis. The lack of a statistically-significant correlation between PET uptake and PSMA immunohistochemistry is notable. This may reflect limited sampling, although the complex relationship between tumour microenvironment, vascular permeability and tracer kinetics likely also plays a role. Of note, there is variability in the literature in this regard [ 6 , 10 ]. From a translational perspective, confinement of PSMA-targeted agents to regions of high capillary permeability would preferentially increase absorbed tumour dose in higher-grade regions, while less vascular tumour may be undertreated. Such intratumoural heterogeneity may limit alpha emitters with short tissue ranges (50–100 µm). In contrast, the beta-emitter [177Lu], with a longer range (~ 0.7–2 mm), may better address heterogeneity and has shown safety and efficacy in prostate cancer [ 2 ]. Extrapolation of absorbed [ 68 Ga]-PSMA dose to a theoretical [ 177 Lu]-PSMA dose remains contentious. A recent study questioned the validity of this approach[ 11 ]; However this conclusion was based upon a single patient with metastatic renal cell carcinoma. In the absence of further evidence, the [ 68 Ga]/[ 177 Lu] theranostic paradigm should not be dismissed but warrants further investigation in HGG. Notably, the estimated [¹⁷⁷Lu] tumour doses in this study are similar to those reported in a recent pilot study[ 12 ] and substantially lower than doses delivered by external beam radiotherapy[ 13 ], but fall within the wide range reported for PSMA-targeted theranostic treatment in prostate cancer[ 14 ]. Comparisons between molecular radiotherapy and external beam radiotherapy remain challenging due to differences in dose rate, exposure time, and linear energy transfer. High uptake in salivary tissue may represent a dose-limiting factor, although alternative administration strategies, such as super-selective intra-arterial delivery, may mitigate off-target toxicity[ 15 ]. Conclusion In keeping with the recent literature, this study demonstrated durable but heterogenous uptake of [ 68 Ga]-PSMA-11 in HGG. PSMA tracer uptake qualitatively overlapped with areas of high capillary permeability, and PSMA expression was most consistently seen within areas of necrotic/proliferating endothelium. These findings support the notion that PSMA tracers target regions of high-grade tumour. A moderate [ 177 Lu] tumour dose was extrapolated; however, this theoretical dose is lower than that currently achieved with external beam radiotherapy. This finding, combined with significant off-target salivary gland dose and heterogenous on-target tumour dose, may limit the therapeutic potential of PSMA in HGG, although future studies with longer tracer kinetics and with larger axial field-of-view PET, may add further insights. Declarations Funding: This work was supported by grants from the Royal College of Radiologists, the Radiological Research Trust, and the Wellcome EPSRC Centre for Medical Engineering at King’s College London (203148/Z/16/Z). SYAT was supported by MRC Grant MR/X00841X/1. Competing Interests: The authors declare that they have no competing interests. Author Contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Matthew Benger, Georgios Krokos, Karan Daga, Alan Wright, Istvan Bodi and Thomas Calvert Booth. The first draft of the manuscript was written by Matthew Benger. All authors read and approved the final manuscript. Data Availability: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request, subject to approval by the UK Health Research Authority and Research Ethics Committee. Ethics Approval: This study was performed in accordance with the Declaration of Helsinki. Ethical approval was granted by the UK Health Research Authority and the Yorkshire & The Humber – Leeds West Research Ethics Committee (REC reference: 23/YH/0087). Consent to Participate: Written informed consent was obtained from all individual participants included in the study. Consent for Publication: The authors affirm that written informed consent was obtained for publication of all participant images and data included in this manuscript. References Poon MTC, Sudlow CLM, Figueroa JD, et al. Longer-term (≥ 2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: a systematic review and meta-analysis. Sci Rep. 2020;10:11622. Uemura M, Watabe T, Hoshi S, et al. The current status of prostate cancer treatment and PSMA theranostics. Ther Adv Med Oncol. 2023;15:17588359231182293. Holzgreve A, Biczok A, Ruf VC, et al. PSMA expression in glioblastoma as a basis for theranostic approaches: a retrospective, correlational panel study including immunohistochemistry, clinical parameters and PET imaging. Front Oncol. 2021;11:646387. Unterrainer M, Niyazi M, Ruf V et al. December. The endothelial prostate-specific membrane antigen is highly expressed in gliosarcoma and visualized by [ 68 Ga]-PSMA-11 PET: a theranostic outlook for brain tumor patients? Neuro-Oncology, 19, Issue 12, 2017, Pages 1698–9. Marafi F, Sasikumar A, Fathallah W, Esmail A. 18F-PSMA 1007 Brain PET/CT Imaging in Glioma Recurrence. Clin Nucl Med. 2020;45(1):e61–2. van Lith SAM, Pruis IJ, Tolboom N, et al. PET Imaging and Protein Expression of Prostate-Specific Membrane Antigen in Glioblastoma: A Multicenter Inventory Study. J Nucl Med. 2023;64(10):1526–31. Peters SMB, Hofferber R, Privé BM, et al. [ 68 Ga]Ga-PSMA-11 PET imaging as a predictor for absorbed doses in organs at risk and small lesions in [ 177 Lu]Lu-PSMA-617 treatment. Eur J Nucl Med Mol Imaging. 2022;49(4):1101–12. 10.1007/s00259-021-05538-2 . Verma P, Malhotra G, Goel A, et al. Differential Uptake of 68Ga-PSMA-HBED-CC (PSMA-11) in Low-Grade Versus High-Grade Gliomas in Treatment-Naive Patients. Clin Nucl Med. 2019;44(5):e318–22. Nørøxe DS, Poulsen HS, Lassen U. Hallmarks of glioblastoma: a systematic review. ESMO Open, 1, Issue 6, 2016, e000144, ISSN 2059–7029. Pruis IJ, van Dis V, Maas SLN, Balvers RK, van den Bosch TPP, Segbers M, Veldhuijzen van Zanten SEM. PSMA radioligand uptake correlates with PSMA expression in high-grade glioma and brain metastasis: insights from a prospective PET-MRI guided multiregional biopsy study. Eur J Nucl Med Mol Imaging. 2025;52(13):4870–81. 10.1007/s00259-025-07338-4 . Bogsrud TV, Engelsen O, Lu TTT, Stensvold A, et al. All that glitters is not gold: high uptake on PSMA PET in non-prostate cancers does not mean that treatment with [ 177 Lu]Lu-PSMA-radioligand will be successful. EJNMMI Res. 2024;14(1):95. 10.1186/s13550-024-01156-9 . Graef J, Bluemel S, Brenner W, et al. [ 177 Lu]Lu-PSMA Therapy as an Individual Treatment Approach for Patients with High-Grade Glioma: Dosimetry Results and Critical Statement. J Nucl Med. 2023;64(6):892–5. Khan L, Soliman H, Sahgal A, et al. External beam radiation dose escalation for high grade glioma. Cochrane Database Syst Rev. 2020;5(5):CD011475. 10.1002/14651858.CD011475.pub3 . PMID: 32437039; PMCID: PMC7389526. Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, Schottelius M, Mueller D, Klette I, Wester HJ. 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med. 2016;57(7):1006–13. 10.2967/jnumed.115.168443 . Pruis IJ, van Doormaal PJ, Balvers RK et al. Potential of PSMA-targeting radionuclide therapy for malignant primary and secondary brain tumours using super-selective intra-arterial administration: a single centre, open label, non-randomised prospective imaging study eBioMedicine, 102, 105068. Supplementary Files EJNMMIPPSMAHGGstudySupplementary.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 21 Jan, 2026 Reviewers invited by journal 21 Jan, 2026 Editor assigned by journal 16 Jan, 2026 First submitted to journal 15 Jan, 2026 You are reading this latest preprint version 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. 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09:50:02","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":31792,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/209f745759718d8a232def47.png"},{"id":101073529,"identity":"92cc0d63-5b05-4b70-a7e5-6d43fa6d0c64","added_by":"auto","created_at":"2026-01-25 10:16:44","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":481373,"visible":true,"origin":"","legend":"","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/ab2f57198cbeb51280707218.png"},{"id":101073534,"identity":"be2e661e-85a0-4cae-8770-0f44842b6a2c","added_by":"auto","created_at":"2026-01-25 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10:16:44","extension":"html","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71640,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/a8faff3e9d3857364f73b78a.html"},{"id":101073521,"identity":"732cd947-0f26-4580-ab21-17c41c245238","added_by":"auto","created_at":"2026-01-25 10:16:44","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":246217,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of injected dose (%ID) (left) and mean Standardised Uptake Value (SUV\u003csub\u003emean\u003c/sub\u003e) (right) within the enhancing part of the tumour (as defined by gadolinium-enhanced \u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e-weighted images).\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/2461a359406bc2bbe4d85314.jpeg"},{"id":101073522,"identity":"0a971ce6-ff6e-4e7b-9101-5fceff740f18","added_by":"auto","created_at":"2026-01-25 10:16:44","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1963374,"visible":true,"origin":"","legend":"\u003cp\u003eFor each patient: axial gadolinium-enhanced \u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e-weighted image (\u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e+c)\u003cem\u003e \u003c/em\u003e(upper left panels), axial [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 PET (upper right panels), axial \u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e+c with co-registered [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 PET (upper middle panels), relative cerebral blood volume (rCBV) (lower left panels), K\u003csub\u003etrans \u003c/sub\u003e(lower middle panels) and V\u003csub\u003ee\u003c/sub\u003e (lower right panels). A high uptake region of apparent tumour invasion (white arrow) shows only faint gadolinium enhancement with raised K\u003csub\u003etrans\u003c/sub\u003e/V\u003csub\u003ee\u003c/sub\u003e and equivocal rCBV. There is visual overlap between regions of high K\u003csub\u003etrans\u003c/sub\u003e/V\u003csub\u003ee\u003c/sub\u003e and tracer uptake. PSMA, like perfusion and permeability MRI, may provide information that is complementary to \u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e+c in terms of identifying regions of higher-grade tumour.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/b54e2f6e73003bc8af880851.jpg"},{"id":101073523,"identity":"529356da-9f78-4741-a282-3e6c012ff04b","added_by":"auto","created_at":"2026-01-25 10:16:44","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":517491,"visible":true,"origin":"","legend":"\u003cp\u003eConsecutive sections from representative patient with haematoxylin and eosin staining (Panel A), Prostate-Specific Membrane Antigen (PSMA) staining (Panel B) and CD34 staining (Panel C). There is high grade glioma with thrombotic and proliferating vessels (Panel A) and marked PSMA staining (Panel B) in CD34-positive endothelial cells (Panel C).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/6fd5951e5f439e65e54e2675.jpg"},{"id":101296671,"identity":"2d0a4afa-c71d-43b5-b958-a5d5b1469ef1","added_by":"auto","created_at":"2026-01-28 09:18:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3394913,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/a4e9f7a9-c7bd-4625-a91d-40cc55f5535b.pdf"},{"id":101205322,"identity":"38cce2a6-73ea-459b-91da-59a04b443b73","added_by":"auto","created_at":"2026-01-27 09:49:02","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":204810,"visible":true,"origin":"","legend":"","description":"","filename":"EJNMMIPPSMAHGGstudySupplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8603380/v1/bf6353fe982562c4cca91801.docx"}],"financialInterests":"","formattedTitle":"Dosimetry and immunohistochemistry study to establish radiolabelled prostate-specific membrane antigen (PSMA) as a potential theranostic target in high-grade glioma treatment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHigh-grade glioma (HGG) is incurable with a life expectancy of under two years[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. \u0026lsquo;Theranostic\u0026rsquo; radiotherapy uses a targeted radionuclide to confirm the presence, concentration and distribution of a target protein (using a gamma or positron emitter) as a condition for targeted radionuclide therapy (using an alpha or beta emitting analogue). This strategy has shown safety and efficacy in metastatic prostate cancer by targeting prostate-specific membrane antigen (PSMA)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eImportantly, PSMA has been reported to be upregulated in HGG[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Following single case studies[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], a recent multi-centre study demonstrated specific uptake of a PSMA-targeted radionuclide, [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11, in HGG using PET-MRI and endothelial expression of PSMA in targeted brain biopsies[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. We prospectively investigated the use of [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 in UK HGG patients to add to the limited global evidence. Specific objectives were to establish dosimetry; calculate theoretical deliverable tumour doses for a potential therapeutic radionuclide; and assess PSMA immunohistochemistry in targeted intra-operative HGG biopsies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThree HGG patients were enrolled consecutively in a prospective study at King\u0026rsquo;s College NHS Foundation Trust, UK. All three patients had a new presumed HGG diagnosis based on clinical and imaging findings and had not undergone any prior treatment.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePET-MR scanning\u003c/h3\u003e\n\u003cp\u003eIn the interval between receiving a diagnosis of likely HGG and surgery, patients underwent a 75 min dynamic PET-MRI study with injection of 174\u0026ndash;188 MBq [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 (t\u0026thinsp;=\u0026thinsp;0) on a Biograph mMR scanner (Siemens Healthineers, Erlangen, Germany) followed by a 10, 20 and 40 min static scan at 120, 180 and 240 min post-injection (Supplementary Data). Imaging acquisition and postprocessing are detailed in the Supplementary Data.\u003c/p\u003e\n\u003ch3\u003ePET-MR Image Analysis\u003c/h3\u003e\n\u003cp\u003eStandardised Uptake Values (SUV) were calculated from regions of interest (ROI) and semi-quantitative analysis of tumour uptake derived. TBR\u003csub\u003emax\u003c/sub\u003e was calculated by dividing SUV\u003csub\u003emax\u003c/sub\u003e of tumour by SUV\u003csub\u003emean\u003c/sub\u003e of the corresponding contralateral region of brain parenchyma. The target-to-off target ratio was calculated by dividing tumour SUV\u003csub\u003emax\u003c/sub\u003e by the mean SUV\u003csub\u003emean\u003c/sub\u003e from the left and right parotid glands using a 10 mm diameter sphere placed at their centre. All quantitative image analysis was performed on MIM version 7.0 (MIM Software Inc., Beachwood, USA). To assess any differences in the distribution of post-gadolinium enhancement and PSMA uptake in the tumours, the overlap of contrast enhancement on \u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u0026thinsp;+\u0026thinsp;c\u003c/sub\u003e and tracer uptake on the co-registered PET study was assessed by two neuroradiologists (UK Fellow (US Fellow equivalent); 5-years neuroimaging experience. UK Consultant (US Attending equivalent); 20-years neuroimaging experience).\u003c/p\u003e\n\u003ch3\u003eDosimetry\u003c/h3\u003e\n\u003cp\u003eMotion correction was performed by rigidly registering the dynamic and late static PET images to the PET\u003csub\u003e60\u0026thinsp;\u0026minus;\u0026thinsp;75\u003c/sub\u003e reconstruction. Regions of the whole-tumour, necrotic core, enhancing rim, and salivary/lacrimal glands were delineated using the co-registered PET\u003csub\u003e60\u0026thinsp;\u0026minus;\u0026thinsp;75\u003c/sub\u003e and T\u003csub\u003e1\u0026thinsp;+\u0026thinsp;c\u003c/sub\u003e image. Time-activity curves (TACs) from 0-240 min were generated for each ROI. Physical decay was assumed from 240 min post-injection and the time-integrated activity coefficients (TIACs) were estimated using the trapezoidal method having expressed TACs to values of proportion of injected dose (%ID). TACs were decay-corrected to the point of injection and recalculated using the t\u0026frac12; of [\u003csup\u003e177\u003c/sup\u003eLu] (6.643 days) to estimate TIACs as performed by Peters \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Tracer uptake beyond 240 min was assumed at equilibrium and only the physical decay of the isotope was further considered in dosimetry calculations. Olinda 1.1 (Hermes, Stockholm, Sweden) was used to estimate tumour and salivary gland doses.\u003c/p\u003e\n\u003ch3\u003eImmunohistochemistry\u003c/h3\u003e\n\u003cp\u003eThree patients underwent two, three and five brain tumour biopsies respectively using intra-operative neuronavigation (StealthStationTM S8 Navigation Platform, Medtronic, Minneapolis, USA), targeting regions of tumour with varying PET tracer uptake. The number of biopsies performed were determined preoperatively according to safety criteria for tissue sampling. Samples were formalin-fixed and immunostained with mouse anti-PSMA (3E6, Agilent Technologies, Santa Clara, USA) and mouse anti-CD34 antibodies (QBEnd/10, Ventana Medical Systems, Tucson, USA). Sections were analysed by a neuropathologist (UK Consultant (US Attending equivalent); 15 years neuropathology experience) with endothelial intensity quantified using a 5-point visual Likert scale (0 \u0026ndash; none, 1 \u0026ndash; mild, 2 \u0026ndash; moderate, 3 \u0026ndash; high, 4 \u0026ndash; very high).\u003c/p\u003e \u003cp\u003eStatistical analysis was performed using GraphPad Prism (Version 10.3.1). A P value of \u0026lt;\u0026thinsp;0.05 was set to determine statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eUptake of PSMA in tumour\u003c/h2\u003e \u003cp\u003eIn all three patients, tumour %ID and SUV\u003csub\u003emean\u003c/sub\u003e increased up to ~\u0026thinsp;70 min then remained constant up to 240 min (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e[\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 demonstrated heterogeneous uptake in solid tumour with no uptake within cavities (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Regions of increased PSMA uptake generally enhanced on \u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;c. Interestingly, in one patient there was a region of high uptake with only faint gadolinium enhancement (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003erCBV mildly increased within enhancing tumour for patients 1 and 3, without clear overlap with high SUV regions. Although there are insufficient data for quantitative correlation between tracer uptake and K\u003csub\u003etrans\u003c/sub\u003e/V\u003csub\u003ee\u003c/sub\u003e parameters, regions of high K\u003csub\u003etrans\u003c/sub\u003e and V\u003csub\u003ee\u003c/sub\u003e appeared to show high tracer uptake (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOverall, there was a moderate tumour SUV\u003csub\u003emax\u003c/sub\u003e (4.20 \u0026minus;\u0026thinsp;10.95) and SUV\u003csub\u003emean\u003c/sub\u003e (1.44\u0026ndash;4.43), and a high TBR\u003csub\u003emax\u003c/sub\u003e (60\u0026ndash;183) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Off-target uptake in the salivary/lacrimal glands and retropharyngeal tissue ranged from 0.026\u0026ndash;0.075 mGy/MBq (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), corresponding to a dose range of 0.85\u0026ndash;2.59 mGy/MBq when extrapolated to equivalent [\u003csup\u003e177\u003c/sup\u003eLu]-PSMA-11 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient age/sex, histopathological diagnosis (using the 2021 WHO brain tumour classification), tumour volume, SUV\u003csub\u003emax\u003c/sub\u003e, SUV\u003csub\u003emean\u003c/sub\u003e, TBR\u003csub\u003emax\u003c/sub\u003e and target to off-target ratio as estimated from PET\u003csub\u003e60\u0026thinsp;\u0026minus;\u0026thinsp;75\u003c/sub\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (years)/Sex (M/F)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHistopathology Diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTumour volume (ml)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eTumour SUV\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eTumour SUV\u003csub\u003emean\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eTBR\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eTarget to off-target ratio\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGlioblastoma IDH WT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDiffuse paediatric-type HGG, H3 WT, IDH WT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e5.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e1.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGlioblastoma IDH WT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e10.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e4.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eAbbreviations: SUV\u0026thinsp;=\u0026thinsp;Standardised Uptake Value; TBR\u0026thinsp;=\u0026thinsp;tumour-to-background ratio; HGG\u0026thinsp;=\u0026thinsp;High-Grade Glioma; IDH\u0026thinsp;=\u0026thinsp;Isocitrate Dehydrogenase; WT\u0026thinsp;=\u0026thinsp;Wild Type; H3\u0026thinsp;=\u0026thinsp;histone H3.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDose range to on-target and off-target tissues after [68Ga]-PSMA-11 injection as estimated from PET60-75 and extrapolated for [177Lu]-PSMA-11.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDose for [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11\u003c/p\u003e \u003cp\u003e(mGy/MBq)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDose for [\u003csup\u003e177\u003c/sup\u003eLu]-PSMA-11\u003c/p\u003e \u003cp\u003e(mGy/MBq)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnhancing Tumour\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.011\u0026ndash;0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38\u0026ndash;1.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParotid glands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.050\u0026ndash;0.062\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.83\u0026ndash;2.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSublingual glands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.026\u0026ndash;0.037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.85\u0026ndash;1.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubmandibular glands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.046\u0026ndash;0.075\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.73\u0026ndash;2.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLacrimal glands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.028\u0026ndash;0.067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.26\u0026ndash;2.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTonsillar and Retropharyngeal tissue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.025\u0026ndash;0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.66\u0026ndash;1.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePSMA immunohistochemistry\u003c/h3\u003e\n\u003cp\u003eIn all three patients, there was significant variation in PSMA staining, which was strongest and most consistent in necrotic/proliferating tumour endothelium (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Conversely, several sections demonstrated only mild staining with numerous negative regions of endothelium. Variable PSMA positivity was seen in non-endothelial regions and considered likely to represent reactive cells.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe intensity of PSMA immunostaining within solid regions of tumour was correlated to [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 uptake, revealing only a weakly positive correlation (Pearson correlation coefficient r\u0026thinsp;=\u0026thinsp;0.27, p\u0026thinsp;=\u0026thinsp;0.45) (Supplementary Data).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrated durable but heterogeneous uptake of a PSMA-directed radionuclide in HGG with a moderately high SUV\u003csub\u003emax\u003c/sub\u003e and a high TBR, consistent with prior studies[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTumour gadolinium enhancement and tracer uptake broadly overlapped. Notably, this is the first study to also demonstrate a region of notable mismatch between [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA uptake and gadolinium enhancement. While faint gadolinium enhancement in this region implies early blood brain barrier breakdown and may at least partly explain increased [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA permeability and retention, the degree of uptake raises the possibility that PSMA PET-MRI could provide complementary information to \u003cem\u003eT\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e\u0026thinsp;+\u0026thinsp;c sequences in identifying regions of higher-grade tumour.\u003c/p\u003e \u003cp\u003eThe qualitative overlap between regions of high tracer uptake and high capillary permeability, together with strong PSMA staining within necrotic/proliferating tumour endothelium (a recognised hallmark of HGG[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]), supports the notion that [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 primarily targets areas of tumour neoangiogenesis.\u003c/p\u003e \u003cp\u003eThe lack of a statistically-significant correlation between PET uptake and PSMA immunohistochemistry is notable. This may reflect limited sampling, although the complex relationship between tumour microenvironment, vascular permeability and tracer kinetics likely also plays a role. Of note, there is variability in the literature in this regard [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFrom a translational perspective, confinement of PSMA-targeted agents to regions of high capillary permeability would preferentially increase absorbed tumour dose in higher-grade regions, while less vascular tumour may be undertreated. Such intratumoural heterogeneity may limit alpha emitters with short tissue ranges (50\u0026ndash;100 \u0026micro;m). In contrast, the beta-emitter [177Lu], with a longer range (~\u0026thinsp;0.7\u0026ndash;2 mm), may better address heterogeneity and has shown safety and efficacy in prostate cancer [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExtrapolation of absorbed [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA dose to a theoretical [\u003csup\u003e177\u003c/sup\u003eLu]-PSMA dose remains contentious. A recent study questioned the validity of this approach[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]; However this conclusion was based upon a single patient with metastatic renal cell carcinoma. In the absence of further evidence, the [\u003csup\u003e68\u003c/sup\u003eGa]/[\u003csup\u003e177\u003c/sup\u003eLu] theranostic paradigm should not be dismissed but warrants further investigation in HGG.\u003c/p\u003e \u003cp\u003eNotably, the estimated [\u0026sup1;⁷⁷Lu] tumour doses in this study are similar to those reported in a recent pilot study[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and substantially lower than doses delivered by external beam radiotherapy[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], but fall within the wide range reported for PSMA-targeted theranostic treatment in prostate cancer[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Comparisons between molecular radiotherapy and external beam radiotherapy remain challenging due to differences in dose rate, exposure time, and linear energy transfer. High uptake in salivary tissue may represent a dose-limiting factor, although alternative administration strategies, such as super-selective intra-arterial delivery, may mitigate off-target toxicity[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn keeping with the recent literature, this study demonstrated durable but heterogenous uptake of [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 in HGG. PSMA tracer uptake qualitatively overlapped with areas of high capillary permeability, and PSMA expression was most consistently seen within areas of necrotic/proliferating endothelium. These findings support the notion that PSMA tracers target regions of high-grade tumour. A moderate [\u003csup\u003e177\u003c/sup\u003eLu] tumour dose was extrapolated; however, this theoretical dose is lower than that currently achieved with external beam radiotherapy. This finding, combined with significant off-target salivary gland dose and heterogenous on-target tumour dose, may limit the therapeutic potential of PSMA in HGG, although future studies with longer tracer kinetics and with larger axial field-of-view PET, may add further insights.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis work was supported by grants from the Royal College of Radiologists, the Radiological Research Trust, and the Wellcome EPSRC Centre for Medical Engineering at King\u0026rsquo;s College London (203148/Z/16/Z). SYAT was supported by MRC Grant MR/X00841X/1.\u003c/p\u003e \u003cp\u003eCompeting Interests:\u003c/p\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003ch2\u003eAuthor Contributions:\u003c/h2\u003e \u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Matthew Benger, Georgios Krokos, Karan Daga, Alan Wright, Istvan Bodi and Thomas Calvert Booth. The first draft of the manuscript was written by Matthew Benger. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability:\u003c/h2\u003e \u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request, subject to approval by the UK Health Research Authority and Research Ethics Committee.\u003c/p\u003e \u003cp\u003eEthics Approval:\u003c/p\u003e \u003cp\u003e This study was performed in accordance with the Declaration of Helsinki. Ethical approval was granted by the UK Health Research Authority and the Yorkshire \u0026amp; The Humber \u0026ndash; Leeds West Research Ethics Committee (REC reference: 23/YH/0087).\u003c/p\u003e \u003cp\u003eConsent to Participate:\u003c/p\u003e \u003cp\u003e Written informed consent was obtained from all individual participants included in the study.\u003c/p\u003e \u003cp\u003e Consent for Publication:\u003c/p\u003e \u003cp\u003e The authors affirm that written informed consent was obtained for publication of all participant images and data included in this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePoon MTC, Sudlow CLM, Figueroa JD, et al. Longer-term (\u0026ge;\u0026thinsp;2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: a systematic review and meta-analysis. Sci Rep. 2020;10:11622.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUemura M, Watabe T, Hoshi S, et al. The current status of prostate cancer treatment and PSMA theranostics. Ther Adv Med Oncol. 2023;15:17588359231182293.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolzgreve A, Biczok A, Ruf VC, et al. PSMA expression in glioblastoma as a basis for theranostic approaches: a retrospective, correlational panel study including immunohistochemistry, clinical parameters and PET imaging. Front Oncol. 2021;11:646387.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUnterrainer M, Niyazi M, Ruf V et al. December. The endothelial prostate-specific membrane antigen is highly expressed in gliosarcoma and visualized by [\u003csup\u003e68\u003c/sup\u003eGa]-PSMA-11 PET: a theranostic outlook for brain tumor patients? Neuro-Oncology, 19, Issue 12, 2017, Pages 1698\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarafi F, Sasikumar A, Fathallah W, Esmail A. 18F-PSMA 1007 Brain PET/CT Imaging in Glioma Recurrence. Clin Nucl Med. 2020;45(1):e61\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Lith SAM, Pruis IJ, Tolboom N, et al. PET Imaging and Protein Expression of Prostate-Specific Membrane Antigen in Glioblastoma: A Multicenter Inventory Study. J Nucl Med. 2023;64(10):1526\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeters SMB, Hofferber R, Priv\u0026eacute; BM, et al. [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET imaging as a predictor for absorbed doses in organs at risk and small lesions in [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 treatment. Eur J Nucl Med Mol Imaging. 2022;49(4):1101\u0026ndash;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00259-021-05538-2\u003c/span\u003e\u003cspan address=\"10.1007/s00259-021-05538-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVerma P, Malhotra G, Goel A, et al. Differential Uptake of 68Ga-PSMA-HBED-CC (PSMA-11) in Low-Grade Versus High-Grade Gliomas in Treatment-Naive Patients. Clin Nucl Med. 2019;44(5):e318\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eN\u0026oslash;r\u0026oslash;xe DS, Poulsen HS, Lassen U. Hallmarks of glioblastoma: a systematic review. ESMO Open, 1, Issue 6, 2016, e000144, ISSN 2059\u0026ndash;7029.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePruis IJ, van Dis V, Maas SLN, Balvers RK, van den Bosch TPP, Segbers M, Veldhuijzen van Zanten SEM. PSMA radioligand uptake correlates with PSMA expression in high-grade glioma and brain metastasis: insights from a prospective PET-MRI guided multiregional biopsy study. Eur J Nucl Med Mol Imaging. 2025;52(13):4870\u0026ndash;81. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00259-025-07338-4\u003c/span\u003e\u003cspan address=\"10.1007/s00259-025-07338-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBogsrud TV, Engelsen O, Lu TTT, Stensvold A, et al. All that glitters is not gold: high uptake on PSMA PET in non-prostate cancers does not mean that treatment with [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-radioligand will be successful. EJNMMI Res. 2024;14(1):95. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13550-024-01156-9\u003c/span\u003e\u003cspan address=\"10.1186/s13550-024-01156-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraef J, Bluemel S, Brenner W, et al. [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA Therapy as an Individual Treatment Approach for Patients with High-Grade Glioma: Dosimetry Results and Critical Statement. J Nucl Med. 2023;64(6):892\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan L, Soliman H, Sahgal A, et al. External beam radiation dose escalation for high grade glioma. Cochrane Database Syst Rev. 2020;5(5):CD011475. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/14651858.CD011475.pub3\u003c/span\u003e\u003cspan address=\"10.1002/14651858.CD011475.pub3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 32437039; PMCID: PMC7389526.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, Schottelius M, Mueller D, Klette I, Wester HJ. 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med. 2016;57(7):1006\u0026ndash;13. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2967/jnumed.115.168443\u003c/span\u003e\u003cspan address=\"10.2967/jnumed.115.168443\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePruis IJ, van Doormaal PJ, Balvers RK et al. Potential of PSMA-targeting radionuclide therapy for malignant primary and secondary brain tumours using super-selective intra-arterial administration: a single centre, open label, non-randomised prospective imaging study eBioMedicine, 102, 105068.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-physics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejph","sideBox":"Learn more about [EJNMMI Physics](http://ejnmmiphys.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejph/default.aspx","title":"EJNMMI Physics","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Theranostic, High-Grade Glioma (HGG), PSMA, PET-MRI","lastPublishedDoi":"10.21203/rs.3.rs-8603380/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8603380/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Prostate-specific membrane antigen (PSMA) is upregulated in high-grade glioma (HGG). This study aimed, firstly, to establish dosimetry for the radionuclide [68Ga]-PSMA-11 in HGG patients; secondly, to determine theoretical tumour doses for [177Lu]-PSMA, a potential therapeutic radionuclide; thirdly, to assess PSMA immunohistochemistry in targeted intra-operative HGG biopsies. Three HGG patients underwent PET-MRI after injection of 185 MBq [68Ga]-PSMA-11. Targeted intra-operative HGG biopsies were immunostained for PSMA and endothelium (CD34). There was durable, heterogeneous uptake of [ 68Ga]-PSMA-11 with moderate SUVmax (4.2-5.0) and high TBR (60-183). [68Ga]-PSMA-11 delivered a tumour dose of 0.01-0.03 mGy/MBq corresponding to 0.38-1.10 mGy/MBq for [177Lu]-PSMA. PSMA staining was predominantly seen in necrotic/proliferating CD34-positive cells. HGGs exhibited moderate and heterogeneous [68Ga]-PSMA-11 uptake, corresponding to a theoretical [177Lu] tumour dose lower than conventional external beam radiotherapy but within the range used for theranostic treatment in prostate cancer. PSMA staining was most prevalent in regions of tumour with necrotic/proliferating endothelium.","manuscriptTitle":"Dosimetry and immunohistochemistry study to establish radiolabelled prostate-specific membrane antigen (PSMA) as a potential theranostic target in high-grade glioma treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-25 10:16:39","doi":"10.21203/rs.3.rs-8603380/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-01-21T10:15:45+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-21T09:58:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-16T08:49:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Physics","date":"2026-01-15T20:04:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-physics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejph","sideBox":"Learn more about [EJNMMI Physics](http://ejnmmiphys.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejph/default.aspx","title":"EJNMMI Physics","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e6396cd0-76bd-4fee-b758-13f2e42a416c","owner":[],"postedDate":"January 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-09T10:24:02+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-25 10:16:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8603380","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8603380","identity":"rs-8603380","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}