Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) represent one of the key targets in the research field of intracellular signaling related to the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). Hence, non-invasive imaging of this enzyme class by positron emission tomography (PET) using appropriate isoform-selective PDE radioligands is gaining importance. This methodology enables the in vivo diagnosis and staging of numerous diseases associated with altered PDE density or activity in the periphery and the central nervous system as well as the translational evaluation of novel PDE inhibitors as therapeutics. In this follow-up review, we summarize the efforts in the development of novel PDE radioligands and highlight (pre-)clinical insights from PET studies using already known PDE radioligands since 2016.

An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands

“…Positron emission tomography (PET) is a molecular imaging technique that allows quantification of biochemical targets and processes in vivo. PET can be valuable in preclinical and clinical drug development because it can provide critical information about target engagement and occupancy by a drug candidate under specific dose regimens. , The development of radioligands for PET imaging of various PDE enzymes is an active area of research that has provided significant advances for imaging PDEs in families 2, 5, 7, and 4. , At a few research institutes, PDE4 has been imaged in human subjects with PET using the pan-subtype-selective radioligand [ 11 C]­( R )-rolipram. − A PDE4B-prefering PET radioligand, code-named [ 18 F]­PF-06445974, has been developed recently and applied in human study. − However, so far, there is no successful PDE4D-selective radioligand. Recently, we have been seeking to develop PDE4D subtype-selective PET radioligands.…”

Radiosynthesis and Preclinical Evaluation of an 18F-Labeled Triazolopyridopyrazine-Based Inhibitor for Neuroimaging of the Phosphodiesterase 2A (PDE2A)

“…So far, all intentions to develop PDE2A specific radiopharmaceuticals are on the basis of PDE-targeted therapeutics with low-molecular weight mainly acting as inhibitors via binding to the substrate binding pocket at the catalytic site of the enzymes [ 1 , 13 , 14 ]. In brief, despite numerous efforts during the last years, the imidazolotriazine derivative [ 18 F]PF-05270430 remains so far the most advanced tracer with preclinical and first in human studies reported already in 2016 [ 15 , 16 ].…”