Clinical Evaluation of PET Radiotracers

National Institute Of Mental Health

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Abstract

Clinical studies are performed under NCT protocols 02743377, 03912428, 03324646, 04396873, 03958630, 04582916, 05522673 , 05062083, 05547880, 05564429, and 05703685 1) PET Imaging of COX-2 in healthy human brain. As outlined in past annual reports, for several years we have focused on developing much-needed, effective, sensitive, and reliable radioligands to image neuroinflammation. Our recent efforts have focused on the cyclooxygenase (COX) system, which comprises two isoforms: COX-1 and COX-2. Both are important targets for neuroinflammatory biomarkers in neuropsychiatric disorders. We developed the direct-acting radioligand [11C]PS13 to measure COX-1 in human and nonhuman primates. In a series of rodent, non-human primate, and human studies outlined in previous annual reports, we confirmed that [11C]PS13 is fully ‘fit for purpose’ to measure COX-1 density in patients, especially those suspected of having neuroinflammation, making it a highly useful novel tool for studying neuroinflammation. We also developed [11C]MC1, which is highly potent and selective for COX-2 compared to COX-1. As reported in past annual reports, we previously found that [11C]MC1 was the first PET radioligand to successfully image and quantify COX-2 upregulation in living nonhuman primate brain after lipopolysaccharide (LPS)-induced neuroinflammation. In a subsequent study, higher [11C]MC1 uptake was observed in the symptomatic joints of patients with rheumatoid arthritis compared to healthy volunteers. Building on this work, we conducted the first-in-human study to evaluate the sensitivity of [11C]MC1 to detect COX-2 density in healthy human brain. Twenty-seven healthy volunteers were injected with [11C]MC1; 10 of these participants received two PET scans: a baseline study followed by blockade with celecoxib (600mg PO), a preferential COX-2 inhibitor, and 17 participants underwent test-retest imaging. All scans included concurrent arterial sampling. The specificity of [11C]MC1 was also confirmed using transgenic mice expressing human COX-2 gene (hCOX-2 mice). In transgenic hCOX-2 mice, 70-90% of [11C]MC1 brain uptake was blocked by nonradioactive MC1 and celecoxib (a COX-2 selective inhibitor) but not by PS13 (a COX-1 selective inhibitor), thereby confirming specific binding to human COX-2. In study participants, [11C]MC1 efficiently crossed the blood–brain barrier, bound to its designated target, and demonstrated high specificity for human COX-2. [11C]MC1 also had a moderate ratio of specific to background uptake binding potential in cortical regions. Collectively, the results indicate that [11C]MC1 has adequate sensitivity to measure the low density of COX-2 in healthy human brain, suggesting it can also quantify COX-2 elevations expected in human disorders associated with neuroinflammation. Because neuroinflammation plays a critical role in many neurological and psychiatric diseases—including Alzheimer’s disease, Parkinson’s disease, and depression—the availability of tools such as [11C]PS13 and [11C]MC1, which allow researchers to image neuroinflammation in the human brain, may have direct benefits for personalized medicine and therapeutic development. 2) Investigating the utility of the novel PET radioligand [18F]SF51 to image translocator protein 18kDa (TSPO) in human brain. As noted above, for several years, we have focused on developing much-needed, effective, sensitive, and reliable radioligands to image neuroinflammation. Translocator protein 18kDA (TSPO) is the most frequently studied target of neuroinflammation using positron emission tomography (PET), but its limitations have spurred the molecular imaging community to find more promising targets. Thus, we turned our attention to [18F]SF51, which was previously found by our laboratory to display excellent imaging properties for TSPO in mouse and monkey brain. Building on this work, this first-in-human study assessed the performance of [18F]SF51 in human brain and its dosimetry. Seven healthy participants underwent brain PET imaging to measure TSPO binding using a two-tissue compartment model to calculate total distribution volume (VT). Participants were genotyped for the rs6971 TSPO polymorphism to designate them according to their TSPO affinities for second-generation radioligands. This cohort included two high-affinity binders (HABs), three mixed-affinity binders (MABs), and two low-affinity binders (LABs). Two other participants received whole-body scans to assess radiation exposure. Peak brain radioactivity reached a standardized uptake value (SUV) of 1.4 at 3 minutes post-injection, diminishing to 30% of peak by 120 minutes. The average VT for all genotype groups was notably low (<1 mL·cm-3), emphasizing the radioligand's poor binding in brain. [18F]SF51 remained sensitive to the TSPO polymorphism in vivo, as shown by a two-fold difference in VT between HABs and LABs. Collectively, the study highlighted significant discrepancies between the preclinical promise and clinical performance of [18F]SF51 as a TSPO-targeted PET imaging agent. Despite promising rodent and monkey data, [18F]SF51 showed low human TSPO binding and was influenced by the rs6971 polymorphism. In addition, an unexpected species-specific lipophilic radiometabolite in human plasma, absent in non-human primate studies, likely compromised its performance. These findings emphasize the challenges of developing PET agents and underscore the necessity of: 1) cautious extrapolation from animal models to human outcomes; 2) thorough human in vivo characterization, regardless of promising animal results; and 3) detailed radiometabolite analysis across species during development. Collectively, the results from this study underscore the importance of rigorous evaluation in developing reliable PET imaging agents for human use as molecular imaging advances.