Project Summary. As a major cAMP-specific hydrolyzing enzyme, PDE7 plays a significant role in modulating
immune and inflammatory response in a variety of neurodegenerative diseases, including Alzheimer’s disease (AD).
PDE7 treatment not only improved the memory and behavior in transgenic models of AD but also exhibited decreased
brain Aβ deposition, enhanced Aβ degradation, and decreased tau phosphorylation. The mechanism of action was
mediated via the cAMP-specific neuroinmmune response in AD. Positron emission tomograohy (PET) is capable of
quantifying biochemical processes in vivo, and a suitable PDE7 ligand would substantially improve our understanding
of such cAMP-mediated signaling under different pathophysiological AD conditions, otherwise inaccessible by ex vivo
(destructive) analysis. Quantification of PDE7 in living brain by PET would also provide the assessment of distribution,
target engagement and dose occupancy of new PDE7-targeted neurotherapeutics. To date, no successful examples
have been demonstrated to image PDE7 in human, representing a significant deficiency of our ability to study this
target in vivo. Therefore, we propose to develop a novel PDE7 PET ligand that can fill this void as the first successful
and translational imaging tool.
We are the first groups to develop PDE7-specific ligands in cross-species PET studies, including [11C]P7-2104
developed in 2021. However, this ligand was discontinued due to marginal binding specificity in vivo. In our 2nd
generation, we identified a lead molecule, P7-2526, which showed high binding affinity and excellent selectivity. Our
preliminary evaluation confirmed that we have overcome the two major obstacles for PDE7 ligand development by
achieving: 1) substantially-improved binding affinity, representing the best compound to date; and 2) high target
specificity (characteristic high uptake in PDE7-rich striatum and low in PDE7-poor cerebellum/pons, which was
validated by LC-MS and Western blotting). Though P7-2526 is a promising lead for new PDE7-targeted ligands, further
optimization for improved binding specificity with proper brain kinetics are sought for translational cross-species
(rodents and nonhuman primates) imaging studies to achieve optimal PDE7 quantification for drug discovery and
clinical translation for AD patients.
On the basis that P7-2526 serves a validated lead for medicinal chemistry optimization, as specific goals, we will
design and prepare a focused library of PDE7-specific modulators amenable for labeling with 11C or 18F, and evaluate
their ability to quantify PDE7 activity and changes during drug challenge in rodents and nonhuman primates, as well
as autoradiography and biological validation in postmortem human brain tissues. The impact of this work is not only
to develop the first successful high-affinity and selective PDE7 PET ligand for the study of neurodegenerative disease-
related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand
for potential clinical translation and monitor target response of novel neurotherapeutics for neurodegenerative
diseases, including AD.