Preclinical Evaluation of the First Adenosine A₁ Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging

Central adenosine A₁ receptor (A₁R) is implicated in pain, sleep, substance use disorders, and neuro­degenerative diseases, and is an important target for pharmaceutical development. Radio­tracers for A₁R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A₁R during the sleep–awake cycle. Although several human A₁R PET tracers have been developed, most are xanthine-based antagonists that failed to demonstrate competitive binding against endogenous adenosine. Herein, we explored non-nucleoside (3,5-dicyano­pyridine and 5-cyano­pyrimidine) templates for developing an agonist A₁R PET radiotracer. We synthesized novel analogues, including 2-amino-4-(3-methoxy­phenyl)-6-(2-(6-methyl­pyridin-2-yl)­ethyl)­pyridine-3,5-dicarbo­nitrile (MMPD, 22b), a partial A₁R agonist of sub-nanomolar affinity. [¹¹C]22b showed suitable blood–brain barrier (BBB) permeability and test–retest reproducibility. Regional brain uptake of [¹¹C]22b was consistent with known brain A₁R distribution and was blocked significantly by A₁R but not A_2AR ligands. [¹¹C]22b is the first BBB-permeable A₁R partial agonist PET radio­tracer with the promise of detecting endogenous adenosine fluctuations.