Translational Evaluation of PET Radiotracers

National Institute Of Mental Health

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Abstract

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. Human studies were performed under NCT03324646. We developed the direct-acting radioligand 11CPS13 to measure COX-1 in human and nonhuman primates. 11CPS13 was found to be potent (IC501 nM) and selective (>1,000 fold) for COX-1 compared to COX-2. High affinitiesparticularly those in the nanomolar or subnanomolar rangeare desired because they increase specific binding to the target of interest. To briefly summarize our past workmuch of which has been discussed in previous annual reportsboth animal and human studies indicated that 11CPS13 is promising for the in vivo imaging of COX-1. In whole-body scans of rhesus monkeys, 11CPS13 showed significant uptake in organs where COX-1 was expected, including gastrointestinal tract, spleen, kidneys, and brain, indicating appropriate distribution. This uptake was blocked after administration of ketoprofen, a COX-1-specific inhibitor, but not celecoxib, a preferential COX-2 inhibitor, indicating good in vivo pharmacological specificity. Whole-body scans in healthy human volunteers found 11CPS13 uptake in most major organs and subsequent blockade by ketoprofen but not celecoxib, reproducing the appropriate distribution and pharmacological specificity seen in animals. Furthermore, in the brains of healthy human volunteers, 11CPS13 uptake was highest in the hippocampus, occipital cortex, and pericentral cortex, a distribution consistent with that of the COX-1 gene transcript. 11CPS13 also demonstrated good absolute test-retest variability (range 6.0-8.5%) and reliability (intraclass correlation coefficient (ICC) range 0.74-0.87), with no radiometabolite accumulation and excellent time-stability. From the perspective of PET quantitation, these results suggested that 11CPS13 was fully fit for purpose to measure the density of COX-1 and, thus, the density of microglia in health and disease. In a recent study, we confirmed that 11CPS13 was selective for COX-1 in humans and could be used to measure the in vivo potency of non-steroidal anti-inflammatory drugs (NSAIDs). Baseline 11CPS13 whole-body PET scans were obtained in 26 healthy volunteers, 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 and celecoxib is a preferential COX-2 inhibitor; aspirin is a selective COX-1 inhibitor with a distinct mechanism that irreversibly inhibits substrate binding. 11CPS13 was selective for COX-1 in humans, as assessed via its distribution (which reflected that of COX-1 rather than COX-2) and by the much greater potency of ketoprofen compared to celecoxib to inhibit uptake in target organs. Using in vivo uptake in organs or ex vivo uptake in blood cells, 11CPS13 was able to measure the in vivo potencies for COX-1 of NSAIDs that act at the substrate binding site. Taken together, the results suggest that 11CPS13 can be used to determine whether any NSAID, except for aspirin, achieves adequate concentrations to inhibit COX-1 in the target organ, whether located centrally or in the periphery. In our opinion, this suggests that 11CPS13 is capable of quantifying COX-1 in the brain and periphery. 2) The effects of ketamine on phosphodiesterase-4B (PDE4B) binding Phosphodiesterase-4 (PDE4) metabolizes and thereby terminates the actions of the second messenger cyclic adenosine monophosphate (cAMP). Rolipram is a reversible PDE4 inhibitor, and 11C(R)-rolipram binding is positively correlated with cAMP signaling. As described in previous annual reports, our laboratory found that 11C(R)-rolipram binding was globally decreased in unmedicated patients with major depressive disorder (MDD) experiencing a major depressive episode compared to healthy volunteers. As a follow-up, we found that, in individuals with MDD, two months of treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant increased (normalized) 11C(R)-rolipram binding compared to pretreatment values. 11C(R)-rolipram binds to all four subtypes of PDE4: 4A, 4B, 4C, and 4D. While we previously found that the sum of all PDE4 subtypes was decreased during a major depressive episode, some subtypes could be decreased and others increased even though the sum total of all subtypes was decreased. In collaboration with Pfizer and the Karolinska Institutet, we developed the novel radioligand 18FPF06445974 (also called 18FPF974), which is preferential for PDE4B in brain, and investigated its characteristics in rats, nonhuman primates and, for the first time, humans. Moving forward, we are using 18FPF974 to examine changes in the cAMP signaling system in individuals with MDD treated with ketamine. Unlike monoamine-associated therapies such as SSRIs, the rapid-acting antidepressant ketamine is a glutamatergic modulator. Our study will assess the effects of ketamine infusion on the cAMP system in human brain to determine whether ketamines antidepressant effects are at least partially mediated via cAMP signaling. While ketamine is classically considered an NMDA receptor (NMDAR) antagonist, some evidence suggests that its antidepressant effects may occur independently of the NMDAR. Ketamine increases the proliferation of neuronal progenitor cells in an NMDAR-independent manner while also increasing cAMP signaling within 15 minutes. Treatment of C6 glioma cells with ketamine also led to increased cAMP accumulation, as well as subsequent increases in phosphorylated CREB (pCREB) and brain derived neurotrophic factor (BDNF). pCREB translocates to the nucleus where it acts as a transcription factor for genes involved in growth and survival, neuroprotection, and synaptic plasticity, perhaps partly due to the downstream effects of BDNF transcription. CREB is both upregulated and phosphorylated at Ser-133 after chronic antidepressant treatment in animals and cultured cells. This effect was found to be mediated by a ketamine-induced association between Gs with adenylyl cyclase, a mechanism shared by prolonged antidepressant treatment. Given a proposed mechanism demonstrated in cell culture models, as well as the clinically relevant use of ketamine in treatment-resistant patients with MDD, our study will examine changes in the cAMP signaling system in individuals with MDD treated with ketamine. The study seeks to determine: 1) whether decreased 11C(R)-rolipram binding is corrected acutely by ketamine treatment, and 2) whether any such correction correlates with clinical response. The protocol was approved by the IRB on August 18, 2022, and the first participant was scanned on February 10, 2023.