Discovery of Highly Potent Adenosine A₁ Receptor Agonists: Targeting Positron Emission Tomography Probes

Abstract

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the in vivo 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 A1 receptor (A1R) radiotracer, [11C]­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 A1R 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 A1 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 27 and 29) with single-digit nanomolar affinities and good subtype selectivity (A1/A2A selectivity of ∼1000-fold for compound 27 and 29-fold for compound 29). Rapid O-[11C]­methylation provided [11C]27 and [11C]29 in high radiochemical yields and radiochemical purity. However, subsequent brain PET imaging in rodents showed poor brain permeability for both radioligands. An in vivo 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, in silico 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 A1 radioligands and also highly potent CNS A1AR drugs.

Discovery and Structure–Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists

“…Other successful selective and CNS active A 1 R agonist examples feature conformationally constrained ribose ring systems . Alternatively, non-nucleoside 3,5-dicyanopyridines have been synthetically optimized to yield potent and A 1 R-selective full agonists, which have also been developed into PET tracers very recently . Rather than modulating receptor activity by orthosteric exogenous agonists, Christopoulos and collaborators have recently presented MIPS521, a positive allosteric modulator of the A 1 R, with which they were able to show in vivo analgesic efficacy in rats .…”

“… 14 Alternatively, non-nucleoside 3,5-dicyanopyridines have been synthetically optimized to yield potent and A 1 R-selective full agonists, which have also been developed into PET tracers very recently. 18 Rather than modulating receptor activity by orthosteric exogenous agonists, Christopoulos and collaborators have recently presented MIPS521, a positive allosteric modulator of the A 1 R, with which they were able to show in vivo analgesic efficacy in rats. 19 Their cryo-EM structural study of the human A 1 R bound to adenosine, MIPS521, and a G i2 protein heterotrimer (PDB code 7LD3 ) revealed the allosteric binding pocket at the lipid interface that could spark structure-based drug design campaigns.…”