Discovery of Subtype Selective Phosphodiesterase-4D (PDE4D) Ligands and Evaluation as Potential Radioligands for Brain Imaging in Monkey and Human

460 Introduction: Phosphodiesterase-4 (PDE4) metabolizes and thereby terminates the actions of the second messenger cyclic adenosine monophosphate (cAMP). Binding of the PDE4 inhibitor [11C](R)-rolipram was previously found to be globally decreased in unmedicated subjects with major depressive disorder (MDD) compared to controls, a finding consistent with the ‘cAMP theory of depression’, which posits that low cAMP signaling causes depression. PDE4 has four different isozymes: A, B, C, and D. PDE4B and PDE4D have the highest expression in the brain and are linked to cognitive deficits as well as major depressive disorder (MDD). This study used positron emission tomography (PET) to assess the newly developed PDE4D-selective radioligand [11C]T-1650 in rhesus monkeys and human. A concomitant goal was to determine whether BPN14770, a PDE4D negative allosteric modulator, could block [11C]T1650 binding, thereby expanding upon previous in vitroresults for PDE4D selectivity and contributing to the evaluation of BPN14770 as a therapeutic candidate. Methods: Two monkeys were examined brain scans for 90-120 minutes in 21-25 frames following a one-minute intravenous bolus injection of [11C]T-1650. To measure enzyme-specific uptake, scans were also performed after injection with selective PDE4D inhibitor, BPN14770. For human, two brain PET scans with [11C]T1650 were performed in each of three healthy controls. Participants completed one baseline scan, one blocked scan 90-180 minutes after one dose of BPN14770, and a second blocked scan after seven doses of BPN14770 administered over three and a half days. In the pharmacokinetic analysis, target enzyme density was quantified as total distribution volume (VT) using the two-tissue compartment model as well as serial concentrations of parent radioligand in arterial plasma. Results: After [11C]T-1650 injection, the tracer readily entered brain and showed widespread distribution, with lower binding in cerebellum in both brain. VT was well identified in all examined brain regions, and VT calculated from the first 90 minutes of scan data fell well within 10% in monkey brain.The extent to which PDE4D was occupied by a blocking agent was estimated graphically using a Lassen plot for several brain regions. PDE4D occupancy was 63%, Nondisplaceable distribution volume (VND) was estimated as 3.6mL/cm3, binding potential (BPND) was 1.2 in monkey brain. For human brain, with use of a standard two-tissue compartment pharmacokinetic model, [11C]T1650 was unable to quantify PDE4D in human brain, possibly due to accumulation of radiometabolites in brain. BPN14770 had a partial blocking effect on PDE4D uptake after a single dose. Taking the limitation of the quantification method into account, the average total distribution volume (VT) for the whole brain decreased by 33%, and the area under the curve of standardized uptake value (SUV) from 60 to 120 minutes (SUV60-120) decreased 30% from baseline after a single dose of BPN14770. Conclusions: [11C]T-1650 was able to successfully image and quantify PDE4D in monkey brain. However, [11C]T1650 was unable to accurately quantify PDE4D in human brain. The PDE4D-selective antagonist BPN14770 blocked PDE4D uptake after a single dose, but the percentage occupancy was difficult to estimate because of the apparent unreliability of calculating VT at baseline and after blockade. Development of an improved radioligand is necessary to accurately quantify PDE4D in the human brain.