Clinical Evaluation of PET Radiotracers

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

Clinical studies are perform under NCT protocols 02743377, 03912428, 03324646, 04396873, 03958630, 04582916, 05522673 , 05062083, 05547880, 05564429, and 05703685 1) Development of 18FPF-06445974 (18FPF974) to quantify phosphodiesterase 4B (PDE4B) in living human brain. 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 lab 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 an 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. We thus sought to establish whether PDE4B, specifically, is decreased during a major depressive episode in unmedicated MDD participants. Such a result would provide a rationale to test a PDE4B inhibitor in MDD patients in the future. In collaboration with Pfizer and the Karolinska Institutet, we developed the novel radioligand 18FPF-06445974 (also called 18FPF974), which is preferential for PDE4B in brain, and investigated its characteristics in rats, nonhuman primates and, for the first time, humans. A concomitant goal was to determine whether 18FPF974 could accurately quantify PDE4 in human brain. Three monkeys and five healthy human volunteers underwent PET scans after intravenous injection of 18FPF974. 18FPF974 readily distributed throughout monkey and human brain and had highest binding in the thalamus. Distribution volume (VT) was well identified but increased by 10% during the terminal portions (40 and 60 mins) of the monkey and human scans, respectively, consistent with radiometabolite accumulation in the brain. Radiochromatographic analyses in knockout mice showed that two efflux transporterspermeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP)completely cleared the problematic radiometabolite but also partially cleared the parent radioligand from the brain. In vitro studies with the human transporters suggested that the parent radioligand was a partial substrate for BCRP and, to a lesser extent, for P-gp. Taken together, the results demonstrated that 18FPF974 successfullybut not completelyquantified PDE4B in human brain. The gold standard compartmental method of analyzing brain and plasma data successfully identified the regional densities of PDE4B, which were widespread and highest in the thalamus, as expected. However, because the radiometabolite-induced error was only about 10%, we believe the radioligand can be extended to clinical studies, providing a powerful tool for developing novel antidepressant agents. In this context, we have begun a study that will compare healthy volunteers and individuals with MDD. The project seeks to determine: 1) whether PDE4B is reduced in individuals with MDD compared to healthy volunteers; 2) the optimal scan length; 3) the test-retest variability; and 4) whether a correlation exists between PDE4B levels and clinical rating scales. Our newly approved protocol will enroll 28 MDD participants and 28 healthy volunteers for scanning with 18FPF974. 2) TSPO to investigate measures of inflammation associated with sleep restriction For many years, my laboratory has been at the forefront of efforts to develop much-needed, effective, sensitive, and reliable radioligands to image neuroinflammation. TSPO is a mitochondrial protein overexpressed in inflammatory cells (activated microglia and reactive astrocytes) and can serve as a biomarker for neuroinflammation. We previously developed 11CPBR28 as a radioligand specific for TSPO and found evidence of widespread or localized neuroinflammation in several disorders. These studies established neuroinflammation as a central avenue of research for our lab, which subsequently expanded to new targets. Though much of our current work examining neuroinflammation focuses on human imaging of the COXs and developing radioligands for novel targets of neuroinflammation, we continue to image TSPO in a sleep restriction study performed in collaboration with Walter Reed. Chronic sleep restriction is common in the general population but especially so in the military, with a significant percentage of soldiers averaging less than four hours of sleep per 24 hours during deployment. Animal studies have shown that sleep restriction is associated with the accumulation of amyloid protein, loss of synapses, and measures of neuroinflammation. However, it remains unknown whether similar effects manifest in sleep-restricted humans. Furthermore, virtually nothing is known about how the putative structural and chemical brain changes associated with sleep loss are reversed by recovery sleep in humans or animals. Guided by findings from the animal literature, we are conducting a first-in-human, state-of-the-art neuroimaging study to index several central physiological processes associated with restricted sleep. This ongoing collaboration with Walter Reed Army Institute of Research (WRAIR) uses PET, MRI, and high-density EEG as well as an array of central and peripheral biomarkers to characterize neuroinflammation, synaptic phagocytosis, and toxic protein accumulation in healthy volunteers. The study involves PET imaging of three targets at three time points: baseline (i.e., before sleep restriction), after one week of sleep restriction (five hours sleep/night), and after two weeks of recovery. The three radioligands are: 18Fflorbetaben for amyloid, 11CUCB-J for synaptic vesicle glycoprotein 2A, and 11CER176 for TSPO; the latter was developed in this lab. The study also seeks to determine the extent to which changes in brain processes correlate with changes in measures of alertness and cognitive performance across sleep restriction and recovery periods. Eighteen healthy male and female volunteers (ages 18-39) will be enrolled in this ongoing study; the first participant was scanned in July 2023. The first phase of the study will identify the physiological mechanisms that best correlate with the duration of sleep restriction and/or the magnitude of performance impairment. Towards this end, we are using a standard, seven-day sleep restriction paradigm to evaluate these relationships at baseline, during sleep restriction, and following short-term and extended recovery periods. By correlating measures of brain chemistry and structure with participants cognitive and behavioral performance over the course of sleep restriction and recovery, we expect to identify at least some of the relevant pathophysiological processes that underlie the deleterious effects of sleep loss. If and when such specific physiological mechanisms are identified, they will suggest potential opportunities to develop targeted drugs or non-pharmacological interventions designed to prevent, mitigate, or facilitate recovery from sleep loss-induced perturbations of the affected brain processes. The study also seeks to determine potential correlations between CNS imaging measures and more easily accessed/less invasive blood biomarkers. Significant associations would suggest a practical means of studying the central effects of acute and chronic sleep restriction beyond the laboratory setting.