Development of a Novel 18F-Labeled Radioligand for Imaging Phosphodiesterase 7 with Positron Emission Tomography.

Abstract

Phosphodiesterases (PDEs) are phosphohydrolytic enzymes responsible for degrading cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), two key second messengers involved in regulating cellular functions. The PDE superfamily can be subdivided into 11 families, with PDE7 playing a crucial role in the proinflammatory process, T-cell activation and proliferation. As such, PDE7 has emerged as a potential therapeutic target for treating inflammatory, immunological, and neurological disorders. To date, only a limited number of PDE7 PET ligands have been reported. These ligands often suffer from low in vivo stability or moderate binding affinity, underscoring the need for highly specific PET radioligands for imaging PDE7 in vivo. Here, we report the development of [¹⁸F]7 ([¹⁸F]P7-2302)-a highly potent (IC₅₀ = 0.18 nM) and selective (>400 folds over other PDEs) PDE7 PET ligand. In vitro autoradiography studies using rat brain sections revealed high PDE7-specific binding for [¹⁸F]7. Notwithstanding these encouraging findings, PET imaging experiments in rats demonstrated low brain uptake of [¹⁸F]7, potentially owing to brain efflux mechanism. Indeed, in vivo studies with combined P-gp and BCRP inhibition substantially improved brain uptake and enabled us to demonstrate in vivo binding specificity of [¹⁸F]7 with PDE7-targeted blockade. Overall, [¹⁸F]7 ([¹⁸F]P7-2302) exhibits promising pharmacological properties and chemical scaffold which holds potential as a PDE7-specific PET radioligand, though further work is required to enhance blood-brain barrier permeability.