Synthesis and pharmacological characterization of [(125)I]MRS1898, a high-affinity, selective radioligand for the rat A(3) adenosine receptor

A known selective agonist of the A(3) adenosine receptors (AR), MRS1898 [(1′R,2′R,3′S,4′R,5′S)-4-{2-chloro-6-[(3-iodophenylmethyl)amino]purin-9-yl}-1-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2,3-diol], was synthesized in radioactive form and characterized pharmacologically. This agonist ligand series, based on nucleoside analogues containing a rigid, bicyclic ring system in place of the ribose moiety, was selected for radiolabeling due to its high A(3)AR affinity across species, with nanomolar binding at both rat and human A(3)ARs. The radioiodination of MRS1898 on its N(6)–3-iodobenzyl substituent was accomplished in 76% radiochemical yield by iododestannylation of a 3-(trimethylstannyl)benzyl precursor. [(125)I]MRS1898 bound to the rat A(3)AR with a K(d) value of 0.17 ± 0.04 nM and a B(max) value of 0.66 ± 0.15 pmol/mg protein. The competition binding profiles for other agonists and antagonists obtained with this radioligand are similar to those previously obtained with other radioligands. The advantages of [(125)I]MRS1898 compared with previously used radioligands are primarily its high selectivity and affinity for the rat A(3)AR and also its facile synthesis and radiochemical stability; however, a relatively high level of nonspecific binding presents a limitation. Thus, we have introduced the first selective radioligand for the rat A(3)AR.