[¹¹C]ZTP-1: An Effective Short-Lived Radioligand for PET of Rat and Monkey Brain Phosphodiesterase Type 4 Subtype B

Abstract

Phosphodiesterase type 4 subtype B (PDE4B) selectively hydrolyzes cyclic adenosine monophosphate to enact numerous downstream signaling events. PDE4B is widely expressed in the brain and is implicated in several neuropsychiatric disorders. Moreover, PDE4B inhibition shows antiinflammatory and antidepressant-like effects in animal studies. [¹⁸F]PF-06445974 has been developed to image human brain PDE4B using PET, thereby providing a tool for pathophysiologic studies and drug development. However, a radioligand labeled with shorter-lived ¹¹C would be an alternative for studies that require more than 1 administration into the same imaging subject on a single day. Methods: 8-Cyclopropyl-10-(3,5-difluoro-4-(methoxy)phenyl)-7,8-dihydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazin-9(6H)-1 (ZTP-1) was identified as possessing many favorable properties for development as a ¹¹C-labeled PET radioligand, including high PDE4B inhibitory potency, moderate computed lipophilicity, and a methoxy group as a potential labeling site. Here, [¹¹C]ZTP-1 was readily obtained by ¹¹C methylation of a synthesized O-desmethyl precursor. PET imaging of rat and rhesus monkey brains was performed with [¹¹C]ZTP-1 at baseline and after administration of PDE4B- and PDE4D-selective inhibitors. Radiometabolite profiles for [¹¹C]ZTP-1 were also determined ex vivo in rat plasma and brains. Results: [¹¹C]ZTP-1 was obtained in a high activity yield and with high molar activity. Rat and monkey PET imaging showed high whole-brain radioactivity uptake with subsequent gradual washout. Challenge experiments verified a high and PDE4B-selective PET signal in rat and monkey brains. Ex vivo rat brain uptake of [¹¹C]ZTP-1 showed less than 1% radiometabolite contamination at 30 min. Total distribution volume measures in monkey brains quickly reached stability. Conclusion: [¹¹C]ZTP-1 is a promising, shorter-lived alternative to [¹⁸F]PF-06445974 for quantifying brain PDE4B in rodents and nonhuman primates with PET and warrants further investigation in humans.