Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 (t1/2 = 20.4 min) for evaluation with PET in monkey. Whereas two of these radioligands did not provide PDE4D-specific signal in monkey brain, two others, [11C]T1660 and [11C]T1650, provided sizable specific signal, as judged by pharmacological challenge using rolipram or a selective PDE4D inhibitor (BPN14770) and subsequent biomathematical analysis. Specific binding was highest in prefrontal cortex, temporal cortex, and hippocampus, regions that are important for cognitive function. [11C]T1650 was progressed to evaluation in humans with PET, but the output measure of brain enzyme density (VT) increased with scan duration. This instability over time suggests that radiometabolite(s) were accumulating in the brain. BPN14770 blocked PDE4D uptake in human brain after a single dose, but the percentage occupancy was difficult to estimate because of the unreliability of measuring VT. Overall, these results show that imaging of PDE4D in primate brain is feasible but that further radioligand refinement is needed, most likely to avoid problematic radiometabolites.

Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer's disease.

Between 20% and 25% of patients diagnosed with Alzheimer's disease (AD) do not have amyloid burden as assessed by positron emission tomography imaging. Thus, there is a need for nonamyloid-directed therapies for AD, especially for those patients with non-amyloid AD. The family of phosphodiesterase-4 (PDE4) enzymes are underexploited therapeutic targets for central nervous system indications. While the PDE4A, B, and D subtypes are expressed in brain, the strict amino acid sequence conservation of the active site across the four subtypes of PDE4 has made it difficult to discover subtype inhibitors. The recent elucidation of the structure of the PDE4 N- and C-terminal regulatory domains now makes it possible to design subtype-selective, negative allosteric modulators (PDE4-NAMs). These act through closing the N-terminal UCR2 or C-terminal CR3 regulatory domains, and thereby inhibit the enzyme by blocking access of cyclic adenosine monophosphate (cAMP) to the active site. PDE4B-NAMs have the potential to reduce neuroinflammation by dampening microglia cytokine production triggered by brain amyloid, while PDE4D-NAMs have potent cognitive benefit by augmenting signaling through the cAMP/protein kinase A/cAMP response element-binding protein (CREB) pathway for memory consolidation. The importance of PDE4D for human cognition is underscored by the recent discovery of PDE4D mutations in acrodysostosis (ACRDY2: MIM 600129), an ultra rare disorder associated with intellectual disability. Thus, the family of PDE4 enzymes provides rich opportunities for the development of mechanistically novel drugs to treat neuroinflammation or the cognitive deficits in AD.