Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and ¹¹C-Labeled Radioligands That Avoid Radiometabolite Contamination.

Abstract

Phosphodiesterase-4D (PDE4D) has emerged as a significant target for treating neuropsychiatric disorders, but no PET radioligand currently exists for robustly quantifying human brain PDE4D to assist biomedical research and drug discovery. A prior candidate PDE4D PET radioligand, namely [¹¹C]T1650, failed in humans because of poor time stability of brain PDE4D-specific signal (indexed by total volume of distribution), likely due to radiometabolites accumulating in brain. Its nitro group was considered to be a source of the brain radiometabolites. <b>Methods:</b> We selected 5 high-affinity and selective PDE4D inhibitors, absent of a nitro group, from our prior structure-activity relationship study for evaluation as PET radioligands. <b>Results:</b> All 5 radioligands were labeled with ¹¹C (half-time, 20.4 min) in useful yields and with high molar activity. All displayed sizable PDE4D-specific signals in rhesus monkey brain. Notably, [¹¹C]JMJ-81 and [¹¹C]JMJ-129 exhibited excellent time stability of signal (total volume of distribution). Furthermore, as an example, [¹¹C]JMJ-81 was found to be free of radiometabolites in ex vivo monkey brain, affirming that this radioligand can provide robust quantification of brain PDE4D with PET. <b>Conclusion:</b> Given their high similarity in structures and metabolic profiles, both [¹¹C]JMJ-81 and [¹¹C]JMJ-129 warrant further evaluation in human subjects. [¹¹C]JMJ-129 shows a higher PDE4D specific-to-nonspecific binding ratio and will be the first to be evaluated.