Recent Developments and Future Perspectives in Magnetic Resonance Imaging and Computed Tomography Contrast Media.

The safety profiles of ICM are well established. This is reflected in many peer-reviewed publications and acknowledged in current radiological CM guidelines. 4 , 5 Adverse drug reactions (ADRs) are either hypersensitivity reactions (HSRs) 6 (also named allergic-like reactions), or local physiological, or vasovagal reactions. 4 , 5 It is important to distinguish these types of reactions. HSRs to ICM manifest similar to allergic reactions seen with other drugs. 4 The best-known risk factors for HSRs are allergic diathesis and especially prior reactions to ICM, particularly to the same ICM. In such cases, re-exposure to the same CM should be avoided and another or, after allergy testing, the best suited ICM can be selected. 5 This underlies the importance of documenting the exact ICM used in the report and patient records. 5 In this context, it is important to determine whether an HSR is the expression of a true allergy, that is, a reaction of the specific immune system based on preexisting antibodies, or a symptom of a nonspecific defense reaction against the triggering (culprit) CM. The French prospective, multicenter CIRTACI study, published in 2018, investigated the incidence and intensity of allergic HSRs in 319 patients after administration of an ICM or a gadolinium (Gd)-based contrast agent (GBCA) using intradermal testing. 6 The more severe the ADR and the more organ systems involved, the greater the likelihood of an allergy to the CM used. 6 The results of this landmark study were incorporated into the 2018 revision of the European Society of Urogenital Radiology (ESUR) guidelines: In patients who have experienced a moderate or severe ADR, blood samples for histamine and tryptase estimation should be obtained 1 and 2 hours (and 24 hours if the patient is still in the hospital) after ICM administration. One to 6 months later, the patient should undergo allergological testing. 5 In recent years, several analyses using data from noninterventional studies of the LOCM iopromide (Ultravist ® , Bayer AG, Leverkusen, Germany) and from its pharmacovigilance database have increased the knowledge about HSRs in general. The risk for HSRs was lower after intra-arterial compared with intravenous (IV) applications, probably related to the more concentrated lung passage of CM after IV applications. 7 Elderly patients and children had a significantly lower rate of HSRs than an adult reference group. 8 Women had a slightly higher risk for HSRs than men while race and region/country had no impact (Fig. 3 ). 9 Although these studies have been conducted with 1 single LOCM, we assume that these characteristics are IOCM/LOCM class effects. Risk of hypersensitivity reactions by region and selected countries in an analysis of 132,850 patient of 4 noninterventional studies with iopromide. Selected countries are the 3 countries with most participants in the analysis. 9 Prewarming of ICM does not seem beneficial in view of tolerance and avoidance of ADRs in general. 10 Overall, current guidelines consider the HSR and acute ADR profiles (events occurring <1 hour after administration) of IOCM and LOCM to be similar. 4 , 5 ICM can impair thyroid function by small amounts of free iodide originating from the formulation and deiodination of the CM in the body (0.01%–0.15% of the organically bound iodine administered). 11 The thyroid gland absorbs the iodide, which can lead to either hyper- or hypothyroidism depending on the patient population and possible underlying disease. Because thyroid hormones are essential for general and brain development, hypothyroidism is of particular concern in neonates and young children (<3 years) exposed to ICM. Hypothyroidism has been observed in a range of 1.0% 12 , 13 –15% 14 of patients and tends to be higher in neonates, particularly preterm neonates, undergoing cardiac catheterization. However, the most recent propensity score matching study found no statistically significant association between ICM exposure and abnormal thyroid levels in children 0–24 months of age. 15 The American College of Radiology (ACR) states that there is convincing scientific evidence to support routine thyroid function testing in children older than 3 months following intravascular administration of ICM. 16 Recently, the US Food and Drug Administration (FDA) revised the prescribing information for all ICM to recommend that decisions about thyroid monitoring after administration to children <3 years of age be based on each child's risk factors, including prematurity, very low birth weight, and underlying medical conditions that affect thyroid function. 17 ICM are predominantly cleared by the renal pathway. Renal safety, particularly in patients with preexisting renal impairment, has therefore been a concern since the introduction of ICM. Current clinical evidence suggests that a smaller number of patients than originally thought are at increased risk of developing contrast-induced acute kidney injury (CI-AKI). 4 , 18 In patients with preexisting kidney damage, fluid replacement is the most effective and widely accepted preventive measure against the potential for further kidney damage from ICM. The landmark AMACING Phase III study 19 investigated the clinical and cost-effectiveness of prophylactic hydration to protect renal function in 660 renally compromised patients (eGFR 30–59 mL per min/1.73 m 2 ) undergoing contrast-enhanced CT angiography. The primary endpoint was the incidence of contrast-induced nephropathy (definition: increase in serum creatinine from baseline ˃25% or ˃44 μmol/L within 2–6 days after CM administration). The overall conclusion was that prophylactic IV hydration may not be necessary in patients with an eGFR higher than 29 mL per min/1.73 m 2 . In 2018, following publication of this study, the ESUR lowered the threshold for recommending hydration in patients at increased risk for the IV use to an eGFR <30 mL/min/1.73 m 2 and for the intra-arterial use with renal first pass to an eGFR 44–30 mL/min/1.73 m 2 . 5 These patients benefit primarily from a rigorous review of the need for the ICM-enhanced procedure, consideration of ICM dose-saving protocols, and discontinuation of concomitant nephrotoxic medications. In at-risk patients with an inadequate hydration status, hydration by drinking water or prophylactic IV hydration may be considered if underlying cardiac disease is not a concern. 19 In the context of the scientific discourse regarding possible differences in the induction of CI-AKI between IOCM and LOCM, all relevant international radiological (ACR 4 and ESUR 5 ), cardiological (American College of Cardiology, American Heart Association, 20 and European Society of Cardiology 21 ), and nephrological (Kidney Disease–Improving Global Outcomes 22 , 23 ) guidelines have meanwhile removed recommendations for the preferred use of IOCM over LOCM in at-risk patients. The most recent change was made in the 2024 revision of the Kidney Disease–Improving Global Outcomes Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease by removing a 2012 recommendation in favor of IOCM. 23 While current radiological guidelines suggest a similar CI-AKI risk profile of IOCM and LOCM, 4 , 5 the authors of a recently published Korean large multicenter study with more than 360,000 propensity score matched patients concluded that despite the minimal risk of CI-AKI in the general population caution is warranted for patients with CKD and eGFR lower than 45 mL/min/1.73 m 2 , or those administered with IOCM. 18 Significant advances in CT scanner technology over the past 2 decades have led to increased efficacy of ICM in CT. This trend is primarily due to the improved technical robustness of x-ray tubes, so that low-kV imaging is now possible in almost all indications and independent from patient body size and constitutions. Spectral CT applications further expand the potential for ICM savings. The improved attenuation of iodine at lower-kV settings translates into increased contrast enhancement, if desired, or allows for a reduction in patient dose. Photon-counting computed tomography (PCCT) is an emerging imaging technology that uses energy-resolving detectors to distinguish x-ray photons based on their energy levels. This capability provides superior spatial resolution, reduced radiation dose, and improved contrast-to-noise ratio (CNR) compared to conventional CT systems. This technology is the subject of a separate article in this issue. PCCT offers several opportunities to improve the use of ICM. 24 The inherently reduced noise of the photon counting technology results in higher CNR, which provides increased sensitivity for detecting ICM or allows for the use of lower doses of ICM, reducing the risk of dose-dependent ADRs. The dual/multienergy capabilities of PCCT can be used for enhanced material decomposition in tissue characterization by isolating iodine- from tissue-specific energy levels (eg, calcium in atherosclerotic plaques from iodine of ICM in the blood), improving diagnostic accuracy in vascular and oncological imaging. The unique capabilities of PCCT open avenues for the development of novel CM based on high atomic number elements such as tungsten, tantalum, or gold. 25 They could provide enhanced contrast at specific energy levels and enable improved material decomposition capabilities compared to iodine. However, the highly optimized properties of ICM, such as their high solubility, excellent tolerability and cost-effective production, have proven to be significant hurdles in the transition of novel CM to clinical application. CEM is an emerging imaging modality that utilizes the principles of standard x-ray mammography (XRM) and the information provided by ICM. CEM provides morphological information on breast lesions by measuring x-ray attenuation on low energy images combined with vascular information by measuring CM flow and accumulation on relatively high energy images. 26 Several studies suggested that CEM may provide increased sensitivity for breast cancer detection compared to XRM, especially in women with dense breast tissue. 26 , 27 In addition, lesion characterization may be improved by highlighting areas of increased vascularity. 28 Finally, compared to breast MRI, CEM is faster, less expensive and typically more accessible, requiring less equipment and specialized training but carries the usual radiation risks for this diagnostic modality. 26 CEM was approved as a new indication for iopromide in the EU, the US and several other countries in 2023. 29 Iohexol (Omnipaque™, GE Healthcare, Chicago, IL) received national CEM approvals in the EU and Korea. Iobitridol (Xenetix ® , Guerbet SA, Villepinte, France) is approved for CEM in a few European countries, such as Italy and France. According to the ACR Appropriateness Criteria 2024 , CEM may be appropriate for adjunctive breast cancer screening in women at intermediate risk for breast cancer with heterogeneous or extremely dense breasts and in women at high risk with nondense or dense breasts (variants 5–7). 30 In an addendum to ACR BI-RADS Mammography 2013 , the ACR recognized that CEM has been shown to be more sensitive than mammography or ultrasound in detecting malignancy. 27 The European Society of Breast Imaging (EUSOBI) concluded that, based on preliminary results, CEM could be considered as an alternative to MRI mammography (MRM) in the presence of contraindications to MRI or to the administration of GBCA. 28 In summary, CEM represents an emerging breast imaging technique that improves diagnostic accuracy as an alternative to MRM. 31

Since their first use in 1988, the number of GBCA applications is estimated to be approximately 900 million by the end of 2024 (Fig. 4 ), with more than 65 million contrast-enhanced scans performed annually. 2 Over the past 20 years, clinical development of new CAs has been limited to indication expansions of existing GBCAs. The lack of new CAs was primarily due to increased uncertainty following safety concerns such as nephrogenic systemic fibrosis (NSF), market saturation, and technical challenges in developing innovative CAs with superior clinical benefit. Nevertheless, a new GBCA, gadopiclenol, was approved in the US in 2022 and in Europe in 2023, with others expected to follow soon. In addition, the superparamagnetic iron oxide particle (SPIO) ferucarbotran is again commercially available in some European countries. Estimation of the usage of gadolinium-based contrast agents between 1988 and end of 2024. *NSF was first detected in 2006 and has been limited to patients with impaired renal function. $ In 2014 Gd presence in the brain was reported with no clinical consequences established. CNS, central nervous system; COVID, coronavirus disease; Gd, gadolinium; NSF, nephrogenic systemic fibrosis. Source: Bayer, data on file. 2 The overall benefit-risk profile of GBCAs is generally favorable across all age groups and approved indications, including potentially vulnerable patient groups, that is, children 32 and the elderly 33 and patients with reduced renal or hepatic function. 34 The most common ADRs are nausea, headache, dysgeusia, flushing, vomiting, dyspnea, and dizziness. A recent safety review examined the extensive clinical experience with 100 million administrations of the established macrocyclic GBCA gadobutrol (Gadovist ® , Bayer AG). 34 Based on data from postmarketing surveillance and clinical trials, the overall reported ADRs were very rare, with a rate of 0.0356%, similar to other established GBCAs. The aforementioned CIRTACI study evaluated both ICM and GBCAs. Interestingly, the likelihood of an allergic reaction and the severity of the reaction were comparable between GBCAs and ICM. 6 Similar to ICM, there is no clinical evidence to suggest that the safety profiles of the approved macrocyclic GBCAs differ from one another. 4 , 5 , 34 – 37 The safety profiles of GBCAs were updated following the report of NSF by Grobner et al in 2006. 38 The association of NSF and GBCA exposure, however, was limited to patients with severe renal impairment. While the exact pathophysiological mechanisms behind NSF are not fully understood, the stability of GBCAs appears to be a crucial factor. Multipurpose linear GBCAs release Gd 3+ ions from their chelate, which increases the risk of NSF, compared to the kinetically more stable macrocyclic GBCAs. This difference in complex stability is due to physicochemical structural differences between linear and macrocyclic GBCAs (Fig. 5 ). Since 2007, NSF cases have decreased significantly because of labeling changes and the implementation of appropriate risk assessment practices. 39 Based on empirical data and theoretical considerations, the ACR Committee on Drugs and Contrast Media, the European Medicines Agency (EMA), and the FDA have classified all GBCAs into different groups based on reported associations with or risk for triggering NSF in patients with severe renal failure. The schemes used by each are similar but not identical. 4 , 5 , 40 Chemical structures of the linear GBCA gadoxetate disodium and the macrocyclic GBCA gadoterate dimeglumine. GBCA, gadolinium-based contrast agent. For the linear liver-specific agent gadoxetate disodium (Eovist ® /Primovist ® , Bayer AG, Fig. 5 ), no confirmed case of NSF has been reported after 20 years of use and almost 12 million administrations. Thus, in July 2024, the ACR reclassified gadoxetate disodium from Group III (limited data regarding NSF risk, but with few, if any, unconfounded NSF cases) to Group II (associated with few, if any, unconfounded NSF cases, a category which includes all approved macrocyclic GBCAs and gadobenate). 4 There is now evidence that traces of Gd are retained in various organs. This was first noted in the bone, 41 in skin in relation to NSF, 38 and in the brain after 2014, when Kanda et al reported a possible association between increased signal intensity (SI) in the dentate nucleus of the brain on unenhanced T1-weighted MRI scans and repeated administration of GBCAs. 42 Subsequent studies, mostly in animals but also some human autopsy studies, 43 have shown that Gd is present in tissues after administration of linear GBCAs, and to a lesser extent after administration of macrocyclic GBCAs, regardless of renal function. 44 – 46 Long-term renal excretion (up to 3 months) of trace amounts of Gd has also been reported. 47 Additional nonclinical studies suggest that macrocyclic GBCAs remain intact and are gradually cleared from the brain over a period of 52 weeks and longer after GBCA administration. In contrast, Gd concentrations remain unchanged and at higher levels after administration of linear GBCAs. 48 , 49 The current knowledge of the long-term presence of Gd in the brain and other tissues has recently been summarized. 44 , 50 Although both the FDA and EMA reviews concluded that a cause-and-effect relationship had not been established between adverse event (AE) reports and the presence of Gd in patients with normal renal function, 51 the EMA suspended the marketing authorization for multipurpose linear GBCAs, while maintaining the restricted use of liver-specific linear GBCAs and a linear GBCA for intra-articular use. 51 The FDA required that the prescribing information for all GBCAs include warnings about the potential risk of Gd retention. 52 The potential effects, if any, of repeated GBCA administration on the musculoskeletal motor system and cognitive function in neurologically healthy adults are currently being evaluated in the ODYSSEY study. This longitudinal, multicenter, prospective, observational study was mandated by the FDA and is being conducted jointly by all GBCA manufacturers. 53 Apart from European countries, linear GBCAs are still approved for use in many countries around the world. Although the clinical consequences of the presence of Gd in the brain and body in patients with normal renal function have not been established to date, the administration of a lower dose of CAs without compromising diagnostic information follows the general pharmacological principle and is in accordance with recommendations of radiological societies and guidelines of health authorities. Against this background, the question was raised whether gadobutrol at a dose lower than the currently recommended standard dose of the established multipurpose GBCAs would allow sufficient clinical efficacy without compromising image quality. Therefore, a prospective, cross-over clinical trial was conducted in 141 patients with known or suspected CNS pathology to determine whether a reduced dose of 0.075 mmol/kg body weight (bw) gadobutrol was noninferior to the standard dose of 0.1 mmol/kg gadoterate with respect to lesion enhancement, lesion border delineation and lesion internal morphology. This study demonstrated noninferiority and gadobutrol at 0.075 mmol/kg bw was approved for CNS imaging in the European Union and other countries. 54 A further step in the direction of dose reduction are GBCAs with significantly increased T1-relaxivities to potentially allowing a lower Gd dose without compromising the diagnostic information such as gadopiclenol (Elucirem ® , Guerbet and Vueway ® , Bracco, Milan, Italy) 55 and gadoquatrane (Bayer AG, in Phase III clinical development). 56 , 57 T1-relaxivity can be increased by changes in molecular design. One possibility is to increase the number q of inner sphere water molecules bound to the Gd 3+ ion from 1 to 2 by reducing the denticity of the ligand. GBCAs with q = 2 provide a significant increase in T1-relaxivity, but the complex stability of such compounds must be carefully evaluated. 58 Gadopiclenol is an example of this strategy (Fig. 6 ). Another approach is to combine several Gd-bearing units into 1 molecule with a lower tumbling rate, which is responsible for the higher relaxivity. Gadoquatrane, with a tetrameric structure containing 4 chelated Gd 3+ ions in a single molecule, is based on the second approach (Fig. 6 ). The influence of the larger molecular diameter on diffusion dependent phenomena is negligible as has been shown in pharmacokinetic (PK) studies (see below). Chemical structures of the new high-relaxivity gadolinium-based contrast agents gadopiclenol and gadoquatrane. Gadopiclenol, a new chemical entity and the first next-generation GBCA, was approved at a dose of 0.05 mmol Gd/kg bw in the US in 2022 and in the EU in 2023 as an extracellular, macrocyclic, multipurpose GBCA for the visualization of lesions in the CNS and other body regions (head and neck, thorax, abdomen, pelvis, and musculoskeletal system), excluding cardiac MRI and MR angiography, in all patients aged 2 years and older. 55 With 12.8 L/(mmol Gd*s) at 1.5T in plasma, the T1-relaxivity of gadopiclenol (q = 2) is higher compared to other macrocyclic GBCAs with q = 1 (3.6 to 4.8 L/(mmol Gd*s)). 55 , 59 Phase II and III clinical trials in the CNS and other body regions have demonstrated noninferiority of 0.05 mmol/kg gadopiclenol compared to 0.1 mmol/kg gadobutrol and gadobenate for lesion visualization parameters. 55 The PK properties of gadopiclenol were studied in volunteers with and without renal impairment and in pediatric patients aged 2 years and older. The PK profile was very similar to that of established macrocyclic GBCAs and no dose adjustment was considered necessary in children. AEs considered to be related to gadopiclenol were observed in 4.2%–4.9% of patients during clinical development and were similar to gadobutrol. 60 , 61 Recently, a publication by Spinazzi et al using spontaneous reporting data showed that after the first year of clinical use no serious AEs and a very low rate of nonserious AEs (0.0036%) were observed after more than 880,000 administrations in the US. 37 Reported AEs were similar to those seen with other GBCAs. Gadoquatrane, an investigational high-relaxivity GBCA, is an extracellular, multipurpose, macrocyclic GBCA with the potential to visualize lesions in the CNS and other body regions including dynamic imaging, that is, MR angiography and cardiac MRI. Gadoquatrane has a plasma T1-relaxivity of 11.8 L/(mmol Gd*s) at 1.5T, 56 which is 2–3 times higher than established marketed macrocyclic GBCAs. In preclinical imaging studies in a rat glioblastoma model, this translated into a noninferior tumor CNR at a gadoquatrane dose of 0.025 mmol Gd/kg bw compared to a 0.1 mmol Gd/kg bw injection of gadoterate. 62 Initial imaging studies were performed in healthy volunteers. Following increasing doses of gadoquatrane (0.01, 0.03, and 0.06 mmol Gd/kg), the relative SI in different areas of interest (CNS, cerebral vessels, and carotid artery) showed dose-dependent increase. Compared with 0.1 mmol Gd/kg bw gadobutrol injection, the estimated comparator-equivalent Gd dose resulting in a similar relative SI for gadoquatrane was less than 0.05 mmol Gd/kg bw in most areas evaluated. The 0.03 mmol Gd/kg bw dose resulted in a peak SI equivalent to the 0.1 mmol/kg bw gadobutrol injection in dynamic CE-MRI. 63 A dose-finding study in patients with known or highly suspected CNS lesions comparing the diagnostic efficacy of 0.04 mmol Gd/kg gadoquatrane with 0.1 mmol Gd/kg bw gadobutrol confirmed the dose of 0.04 mmol Gd/kg bw for the further clinical development. 64 PK studies of gadoquatrane in healthy volunteers of different ethnicities have shown that the dose-normalized PK parameters of gadoquatrane are similar to those of the established multipurpose GBCAs. In early clinical trials, only mild or moderate but no serious AEs were observed with no apparent differences in AE frequency after administration of gadoquatrane or gadobutrol and no increase in AE frequency with increasing gadoquatrane dose. 63 Gadoquatrane is currently being evaluated in 3 pivotal Phase III clinical trials: The QUANTI Pediatric study is evaluating the PKs and safety of gadoquatrane in pediatric patients from birth to <18 years of age. The QUANTI CNS and QUANTI OBR studies are evaluating the efficacy and safety of gadoquatrane in adult patients with known or suspected CNS pathology or pathology in any body region outside the CNS. In all studies, a dose of 0.04 mmol Gd/kg bw gadoquatrane is compared to 0.1 mmol Gd/kg bw macrocyclic GBCA (standard of care). 65 – 67 Another new macrocyclic multipurpose GBCA currently in clinical development is HNP-2006. HNP-2006 (Hana Pharm, Seoul, South Korea) carries a lipophilic side chain and has a T1-relaxivity of 4.5 L/(mmol Gd*s) at 3T in plasma. Its PK and safety profile was evaluated in a Phase I study in healthy volunteers at increasing doses (0.02–0.3 mmol Gd/kg bw). The AEs observed were all mild and increased in number at doses above 0.1 mmol Gd/kg bw. The PK profile of HNP-2006 was similar to that of other extracellular GBCAs with complete renal excretion and a plasma half-life of approximately 2 hours. However, the partial hepatobiliary excretion found in animals was not observed in humans. 68 GBCAs have been the cornerstone of CE MRI for decades. However, increasing discussions about the presence of Gd in the brain and other tissues, even in patients with normal renal function, as well as growing awareness of the presence of anthropogenic Gd in the environment and aquatic systems, have prompted the exploration of alternative paramagnetic elements. Manganese is a naturally occurring element in the human body and diet and is essential for many biological functions, making it inherently biocompatible. Manganese is available from abundant resources that are not limited to a few geographic regions and offers potential for sustainable manganese-based CAs (MBCAs). With 5 unpaired electrons in its high spin state and a long electronic relaxation time, the manganese (II) ion has good paramagnetic properties. Shortly after the introduction of MRI in the 1970s, MnCl 2 was used as one of the first CAs in animal studies 69 setting the stage for a long history of MBCAs in MRI CA research, which has been the subject of several recent reviews. 70 – 72 Most of the investigated linear or macrocyclic Mn 2+ complexes are based on multidentate ligands adapted to the smaller size of the Mn 2+ ion (ionic radius of 83 pm vs. 111 pm for Gd 3+ ) and its reduced coordination number (6–7 vs. 8–9 for Gd 3+ ). 72 They provide T1-relaxivities in the range of current GBCAs, but their complex stabilities are lower than those of GBCAs due to the lower charge of Mn 2+ and the reduced specificity of the ligands over endogenous transition metal ions such as Fe 3+ or Zn 2+ , making them prone to transmetalation. This is partially compensated for by the endogenous nature and lower toxicity of potentially released Mn 2+ ions compared to Gd 3+ ions. Most MBCAs have only been studied in vitro or in a few proof-of-concept imaging studies in animals. However, a few exceptions will be discussed in more detail. Currently, there are 2 extracellular Mn 2+ complexes in clinical development with imaging efficacy and PKs similar to current extracellular GBCAs. The linear Mn-PyC3A (RVP-001, Reveal Pharmaceuticals Inc. Boston) has an EDTA-derived ligand and a T1-relaxivity of 3.8 L/(mmol Mn*s) in plasma at 1.4T (Fig. 7 ). Its stability constant log K MnL is ~14 and is lower than that of Gd-DTPA, but it is more stable to transmetalation by endogenous Zn 2+ ions than Gd-DTPA. 73 A Phase I study evaluated the PKs and safety profile of Mn-PyC3A at single ascending doses of Mn (2, 4, 7, or 12 mg Mn/kg) in healthy volunteers. 74 As expected from preclinical studies, elimination was predominantly via the kidneys but also through the liver. 73 No serious but a few mild AEs were observed following administration of Mn-PyC3A. Patients with CNS lesions are currently enrolled in a Phase II study to evaluate the safety, efficacy and PKs of Mn-PyC3A. 75 Chemical structures of different manganese-based contrast agents. A second investigational extracellular macrocyclic MBCA (GEH200486) is currently being developed by GE Healthcare. A Phase I study evaluated the PKs and safety in healthy volunteers following IV injection of 50–300 μmol Mn/kg bw. The study is reported as completed with 15 of the planned 24 subjects but results have not yet been published. 76 With high stability, biocompatibility and efficient excretion pathways, MBCAs represent a significant step toward a safe and sustainable alternative for GBCAs. Since the advent of clinical MRI, targeted CAs that could overcome the passive and nonspecific distribution of traditional GBCAs have been envisioned by radiologists who wanted to visualize only a specific organ or lesion for early diagnosis, disease staging, therapy monitoring, and image-guided therapy. For nearly 40 years, a large number of potential cellular targets and a variety of binding strategies have been identified. 77 Despite intensive research and successful demonstration in animal models, only a few targeted agents have entered the clinical development phase. The targeted approach faces several obstacles. The target must be accessible by the contrast agent, which is present at a relevant concentration only in the extracellular space. Intracellular targets are very difficult to approach. To obtain visible signal enhancement the contrast agent must be present at high micromolar concentrations and thus the target must be present at similar high local concentration, which is rarely the case, or facilitate local accumulation. In addition, the expression of the target must be lesion or organ specific. Abundant components of the extracellular matrix or accumulating transport systems, such as the organic anion transporting polypeptide in the hepatocytes, which is responsible for the hepatic uptake of gadoxetate or gadobenate are therefore attractive targets. 78 EP-2104R (formerly EPIX Pharmaceuticals, Lexington MA), a fibrin-binding peptide linked to 4 macrocyclic GBCA moieties and designed to visualize vascular thrombi, 79 entered Phase II clinical trials 80 but the development was discontinued in 2009. Another targeted GBCA currently in clinical development is MT218 (Molecular Theranostics, Cleveland, OH), a short peptide linked to a single gadoteridol that targets a tumor-specific variant of fibronectin (EDB-FN), a glycoprotein and a component of the extracellular matrix in aggressive solid tumors that is absent in normal tissues. MT218 has a T1-relaxivity of 6.5 L/(mmol Gd*s) (1.4T, human serum albumin, 37°C), and a moderate binding affinity to EDB-FN (K d 3.5 μM). 81 In animal studies, MT218 has demonstrated the potential to discriminate between aggressive and low-grade prostate cancer at the proposed human dose of 0.04 mmol/kg bw. 82 In a Phase I clinical trial, 83 the PK profile of MT218 was similar to that of gadoteridol and transient mild to moderate AEs were observed in some subjects, primarily in the highest dose group. MT218 is currently being evaluated in a Phase Ib clinical trial in 12 patients with prostate cancer. 84 A nanoparticulate theranostic agent (AGuIX, NH TherAguix, Meylan, France) based on 10 Gd-DOTA moieties attached to a polysiloxane core is currently being investigated in several Phase II clinical trials as a radiosensitizer in the MRI-guided treatment of patients with various malignancies. 85 , 86 The agent has a T1-relaxivity of 8.9 L/(mmol Gd*s) at 3T and, because of its small size (3–5 nm, 8–10 kDa), does not accumulate in the liver but is renally excreted. Its passive accumulation in tumors is based on leaky tumor vasculature, known as enhanced permeability and retention effect and results in a prolonged presence in tumors while the background in surrounding tissues is rapidly cleared. In a Phase I study in patients with brain metastases of various origins, escalating doses of nanoparticles (15–100 mg/kg bw) were administered 2 hours prior to MRI and 4 hours prior to the first of 10 radiation therapy sessions. All metastases showed enhanced SI that correlated with the injected dose. The plasma elimination half-life was approximately 1.3 hours and approximately 54% of the dose was renally excreted after 24 hours. The injection of nanoparticles was well tolerated, and individual analysis of metastases showed a significant correlation between nanoparticle uptake and reduction in metastatic size after radiotherapy; however, a control group without nanoparticle injection was not included in this study. 87 In 1997, the first MBCA, mangafodipir (Teslascan, formerly Nycomed, Oslo, Norway/GE Healthcare, Fig. 7 ), was approved as a liver-specific CA. It is a relatively labile linear Mn 2+ complex of dipyridoxyl diphosphate that rapidly releases the Mn 2+ ions, which are taken up by hepatocytes and lead to signal enhancement of healthy liver tissue. 88 It was withdrawn from the market in 2003 (US) and 2012 (EU). However, several clinical trials have recently been conducted to investigate its use in diagnosis of cardiomyopathies. 89 , 90 Mn 2+ -enhanced MRI after infusion of mangafodipir was superior to late Gd enhancement with gadobutrol in accurately differentiating infarcted, stunned, and viable myocardium. 89 Clinical trials evaluating the safety and diagnostic potential of mangafodipir in patients with AKI to detect early cardiovascular complications 91 and in patients with drug-resistant epilepsy are currently ongoing. 92 Another preparation in clinical development containing Mn 2+ ions is Orviglance, an oral formulation of MnCl 2 with L-alanine and vitamin D3 (Ascelia Pharma, Malmö, Sweden). It is indicated for liver MRI in renally impaired patients for whom GBCAs are contraindicated. A small fraction of the orally administered Mn 2+ ions is absorbed within a few hours and subsequently taken up by hepatocytes, enhancing healthy liver tissue with liver-to-lesion contrast of approximately 30% at 3 hours after dose. 93 Recently, a Phase III study was conducted in 200 patients with known or suspected focal liver lesions and renal impairment. 93 , 94 A major disadvantage of the oral administration is the lack of arterial-phase enhancement, which is often required for more accurate lesion characterization in the liver and is usually part of the imaging sequence with IV injected agents such as gadoxetate disodium. A different approach is being pursued by Spago Nanomedical AB, Lund, Sweden. Spago is developing a complex mixture of Mn 2+ ions with chelating bisphosphonates, cross-linked by Si-O-Si bonds and a coating layer of PEG polymers (SN132D, pegfosimer manganese). The mixture forms small (5–6 nm) particles with a remarkable T1 relaxivity of 33.8 L/(mmol Mn * s) in human serum at 1.5T. The preparation allows visualization of tissues with leaky capillaries (enhanced permeability and retention effect) and is partially renally excreted. 95 In a Phase I clinical trial in 14 patients with breast cancer, the safety, PK, and diagnostic efficacy of pegfosimer manganese were assessed. 96 , 97 Following a 1-hour infusion of 10 or 20 μmol Mn/kg, pegfosimer manganese provided tumor enhancement in the high dose group and was cleared from the circulation with a half-life of a few minutes. Some patients of the lower dose group and all patients of the high dose group experienced a variety of mild to moderate and 1 severe AEs. 97 Because of the observed AEs and enhancement of the liver, the investigators concluded that Mn 2+ ions were released from the contrast agent post injection. A Phase IIa study evaluating the diagnostic value and safety of pegfosimer manganese in participants with suspected endometriosis has been completed, but results have not yet been reported. 98 SPIOs constitute another interesting class of CAs. Their composition, mode of action, properties, and potential applications have recently been reviewed. 99 , 100 Several compounds have been approved for liver and lymph node imaging in the past but were withdrawn from the market in most countries in the first decade of this century. Since 2023, a new presentation of ferucarbotran is available in the EU for liver imaging (Resotran ® , b.e. imaging GmbH, Germany). The main properties of SPIOs are their dominant T2 relaxation and uptake by macrophages of the reticuloendothelial system in the liver, lung, spleen, and bone marrow or lymph nodes, where the particles are completely degraded and transferred into the body's iron pool. Several clinical trials have been conducted over the past 10 years, which are summarized in 2 comprehensive reviews. 100 , 101 Most studies were conducted with MagTrace ® (Endomagnetics Ltd, GB), which was approved as a medical device in the UK in 2011. The 60-nm, carboxydextran-coated particles are used as a magnetic tracer to locate sentinel lymph nodes in patients with breast cancer or other malignancies. They are injected peritumorally by the surgeon during tumor resection and are detected by hand-held, pen-like magnetometer probe (SentiMag ® ). This method has been shown to be noninferior to the radioactive/blue dye method in avoiding unnecessary dissection of all axillary lymph nodes. 102 A SPIO of similar size (45–65 nm), coated with m-PEG silane (MPB-1523, MegaPro Biomedical Ltd, Taiwan) and intended for T2 weighted (T2w) liver imaging after IV injection, has recently completed a Phase II clinical trial in patients with suspected HCC. The preparation caused few mild to moderate AEs and demonstrated visualization of HCC lesions with high predictive value. 103 Ferumoxytol (Ferahaeme, AMAG, Cambridge) is approved for the treatment of iron deficiency in the US but was originally developed as a CA for MRI and is now used off-label for this indication. Ferumoxytol consists of 17- to 31- nm particles coated with polyglucose-sorbitol-carboxymethyl ether and has a long plasma half-life of 10–14 hours. 104 Following several reports of severe hypersensitivity reactions, ferumoxytol was withdrawn from the market in Europe in 2015 105 and the FDA issued a black box warning. Nevertheless, it has been tested since then in several clinical trials as a CA in MR angiography, including detection of cardiac thrombi and atherosclerotic plaques, imaging of CNS tumors, and visualization of inflammation in MS lesions. A few studies have been reported for ferumoxtran-10 (Ferrotran, SPL Medical, Nijmegen, NL), 30-nm particles coated with dextran, which have a long plasma half-life of 25–30 hours. Because of the low relaxivity ratio r2/r1, they provide contrast in T1w and T2w imaging. 106 Ferumoxtran-10 was clinically evaluated in the late 1990s (Sinerem ® , Guerbet) for the detection of metastatic lymph nodes on MRI following IV injection. 107 Because of insufficient diagnostic efficacy, this development was later discontinued 101 but ferumoxtran-10 is now being re-evaluated for the detection of sentinel lymph nodes in patients with pancreatic or prostate cancer. A multicenter Phase III trial in patients with prostate cancer is currently enrolling patients. 108 Preclinical research activities are mainly focused on ultrasmall SPIOs (core <3–5 nm) as blood pool agents for the detection of tumors, inflammation, or atherosclerotic plaques. Because of their low r2/r1 ratio, they provide signal enhancement on T1w images, a clear advantage over the larger-sized SPIOs for T2w imaging. 109 However, the complex design and structure of the proposed nanoparticles may pose significant challenges in meeting the stringent requirements for commercial production of particulate IV drugs. A new and interesting indication for CE-MRI has emerged with a deeper understanding of the glymphatic system (GS) in the brain and its role in neurodegenerative and other neurological diseases. The GS, first described by Iliff et al in 2012, 110 is a clearance pathway in the brain. It relies on the coordinated movement of cerebrospinal fluid and interstitial fluid through perivascular spaces and facilitates the removal of metabolic waste, including amyloid-beta and tau. Disruption of these mechanisms contributes to the accumulation of toxic deposition. The potential of CE-MRI as an important tool to study the function or dysfunction of the GS has recently been reviewed. 111 , 112 Dynamic CE-MRI over several hours typically involves intrathecal injections of GBCAs but studies with IV injection have also been reported in patients with suspected blood-brain barrier leakage. GBCAs are tracers that track cerebrospinal fluid flow, perivascular fluid dynamics, and waste clearance pathways in real time. Several clinical studies have demonstrated impaired glymphatic flow in Alzheimer's disease 113 and Parkinson's disease 114 and in traumatic brain injury, or highlighted increased glymphatic activity during non-REM sleep, and evaluated the effects of interventions, such as sleep improvement or pharmacologic agents, on glymphatic function. Currently, approved GBCAs were not developed for intrathecal administration and carry a black box warning for intrathecal use in the US. Their safety profile after intrathecal administration has been evaluated in a meta-analysis 115 but prospective clinical studies are required to achieve approval and more widespread use in this interesting indication.

Our estimation of the usage of only iso-osmolar CM (IOCM) and low-osmolar CM (LOCM) is 4+ billion applications between 1985 and the end of 2024 (Fig. 1 ). 2 Over the last 10 years, there have been no significant changes in terms of new developments or market entries of iodinated CM (ICM). 3 The chemical structures of 2 typical representatives are depicted in (Fig. 2 ). However, technological advances as well as a better understanding of some safety related aspects also led to new or modified CM applications. Contrast-enhanced mammography (CEM) was approved as a new clinical indication for 3 LOCM in different countries, and a major nephrology guideline updated its recommendations regarding the impact of IOCM on renal function. Estimation of the usage of iso-osmolar and low-osmolar contrast media between 1985 and December 2024. *CI-AKI, contrast-induced acute kidney injury; CIN, contrast-induced nephropathy; COVID, coronavirus disease. Source: Bayer, data on file. 2 Chemical structures of the iso-osmolar contrast medium iodixanol and the low-osmolar contrast medium iopamidol.

Recent advances in CT and MRI CM reflect a dynamic field committed to improving diagnostic accuracy while maintaining a focus on patient safety. Studies underscore the overall safety of CM in clinical use, but continued vigilance and tailored use in vulnerable populations are required. Targeted CM can serve as a transformative leap in personalized medicine, enabling highly specific imaging of pathological processes. The challenge for the future will be to balance safety, diagnostic efficacy, sustainability, and cost-effectiveness while taking advantage of new classes of CM in combination with new imaging technologies and artificial intelligence. Continued interdisciplinary research will be critical to the evolution of CM to ensure that innovations meet the future demands of diagnostic imaging.