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

Central adenosine A, receptor (A(1)R) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for A(1)R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A,R during the sleep-awake cycle. Although several human AIR 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 A(1)R 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 AIR agonist of sub-nanomolar affinity. [C-11]22b showed suitable blood brain barrier (BBB) permeability and test-retest reproducibility. Regional brain uptake of [C-11]22b was consistent with known brain A(1)R distribution and was blocked significantly by A(1)R but not A(2A)R ligands. [C-11]22b is the first BBB-permeable A(1)R partial agonist PET radiotracer with the promise of detecting endogenous adenosine fluctuations.