Clinical Evaluation of PET Radiotracers

National Institute Of Mental Health

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Abstract

Studies were conducted under the following NationalClinicalTrials protocols: NCT02743377, NCT03912428, NCT03324646, NCT04396873, NCT03958630, and NCT04582916. 1) Evaluation of novel PET radioligands for imaging cyclooxygenase (COX)-1 and COX-2 For several years, we have focused on developing much-needed, effective, sensitive, and reliable radioligands to image neuroinflammation. For instance, in 2017, we developed radioligands now widely used for the 18 kDa translocator protein (TSPO). 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. Recognizing that in vivo imaging of COX-1 and COX-2 could be a powerful tool for assessing neuroinflammatory response, we recently developed two PET radioligands: 11C-PS13 for COX-1 and 11C-MC1 for COX-2. We continue to expand this work, which has been described in several of our past annual reports. In human and nonhuman primate whole blood assays, 11C-PS13 was highly potent and selective for COX-1 compared to COX-2, and 11C-MC1 was highly potent and selective for COX-2 compared to COX-1. As reported in past annual reports, we previously found that 11C-PS13 had excellent in vivo selectivity in animal studies. With regard to 11C-MC1, we previously found that it 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 controls. In nonhuman primate brain, specific binding of 11C-MC1 was markedly increased after repeated LPS injection, while that of 11C-PS13 was unchanged. Building on this work, we investigated whether 11C-PS13 could be used to quantify constitutive levels of COX-1 in healthy human brain and found that, indeed, 11C-PS13 binding reflected actual COX-1 density in the human brain. These results from the first-in-human evaluation of the ability of 11C-PS13 to image COX-1 in the brain justified extending the study to disease populations with neuroinflammation and also suggested that, in both nonhuman primates and humans, 11C-PS13 and 11C-MC1 could be used to assess drug delivery and in vivo selectivity in therapeutic trials of nonsteroidal anti-inflammatory drugs (NSAIDs). To test this hypothesis, we conducted a whole-body PET imaging study with 11C-PS13 to evaluate the selectivity of 11C-PS13 binding to COX-1 in humans and assess its ability to measure the in vivo potency of NSAIDs. Twenty-six healthy volunteers enrolled in the study and received baseline 11C-PS13 whole-body PET scans, followed by blocked scans with ketoprofen (n=8), celecoxib (n=8), or aspirin (n=8). Ketoprofen is a highly potent and selective COX-1 inhibitor, celecoxib is a preferential COX-2 inhibitor, and aspirin is a selective COX-1 inhibitor with a distinct mechanism that irreversibly inhibits substrate binding. Because blood cells, including platelets and white blood cells, also contain COX-1, 11C-PS13 uptake inhibition from blood cells was measured in vitro and ex vivo (i.e., using blood obtained during PET scanning). We observed high 11C-PS13 uptake in major organs with high COX-1 density, including the spleen, lungs, kidneys, and gastrointestinal tract. Ketoprofen (1-75mg p.o.) blocked uptake in these organs far more effectively than celecoxib (100-400mg p.o.). Based on the plasma concentration to inhibit 50% of the maximum radioligand binding in the spleen (in vivo IC50), ketoprofen (<0.24M) was >10-fold more potent than celecoxib (>2.5M) as a COX-1 inhibitor, consistent with the in vitro potencies of these drugs for inhibiting COX-1. Blockade of 11C-PS13 uptake from blood cells acquired during the PET scans mirrored that in organs of the body. Interestingly, aspirin (972-1,950mg p.o.) blocked such a small percentage of uptake that its in vivo IC50 could not be determined. Collectively, the results demonstrated that 11C-PS13 selectively binds to COX-1 in humans and was able to measure the in vivo potency of NSAIDs that competitively inhibit arachidonic acid binding to COX-1. These in vivo studies, which reflect the net effect of drug absorption and metabolism in all organs of the body, demonstrated that ketoprofen had unexpectedly high potency, that celecoxib substantially inhibited COX-1, and that aspirin acetylation of COX-1 did not block binding of the representative non-steroidal inhibitor 11C-PS13. The results provide further evidence thatas the first radioligands to act directly on COX-1 and COX-211C-PS13 and 11C-MC1 provide a powerful new research tool for the study of mental disorders associated with neuroinflammation, including dementias and MDD.