Discovery of Highly Potent Adenosine A Receptor Agonists: Targeting Positron Emission Tomography Probes

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the biodistribution of ARs in the central nervous system (CNS), which is of therapeutic interest for various neuropsychiatric disorders. Additionally, radioligands that can image changes in endogenous adenosine levels in different physiological and pathological conditions are still lacking. The binding of known antagonist adenosine A receptor (AR) radiotracer, [C]MDPX, failed to be inhibited by elevated endogenous adenosine in a rodent PET study. Since most of the known AR PET radiotracers were antagonists, we propose that an AR agonist radioligand may possess higher sensitivity to measure changes in endogenous adenosine concentration. Herein, we report our latest findings toward the development of a full agonist adenosine A radioligand for PET. Based on a 3,5-dicyanopyridine template, 16 new derivatives were designed and synthesized to optimize both binding affinity and functional activity, resulting in two full agonists (compounds and ) with single-digit nanomolar affinities and good subtype selectivity (A/A selectivity of ∼1000-fold for compound and 29-fold for compound ). Rapid O-[C]methylation provided [C] and [C] in high radiochemical yields and radiochemical purity. However, subsequent brain PET imaging in rodents showed poor brain permeability for both radioligands. An PET study using knockout mice for MDR 1a/a, BCRP, and MRP1 indicated that these compounds might be substrates for brain efflux pumps. In addition, evaluation using multiparameter optimization identified high molecular weight and high polar surface area as the main molecular descriptors responsible for low brain penetration. These results will provide further insight toward development of full agonist adenosine A radioligands and also highly potent CNS AAR drugs.