A(1) ADENOSINE RECEPTOR ANTAGONISTS AS LIGANDS FOR POSITRON-EMISSION-TOMOGRAPHY (PET) AND SINGLE-PHOTON EMISSION TOMOGRAPHY (SPET)

The high affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX) for the A(1) adenosine receptor (A(1)AR) provides a good lead for developing r adioligands suitable for positron emission tomography (PET) and single -photon emission tomography (SPET). This study tested the hypothesis t hat the kinds of chemical modifications made in the synthesis of CPX a nalogues containing carbon-ii, fluorine-18, or radioiodine will not al ter affinity for the A(1)AR. This report describes the synthesis and r adioligand binding assays of unlabeled CPX analogues having methyl, 2- methoxyethyl, 2-fluoropropyl, or 3-fluoropropyl substituents, respecti vely, at either N-1 (13a-d) or N-3 (8a-d) or an (E)-3-iodoprop-2-en-1- yl substituent at N-3 (8f). Compounds 8d,f and 13b,d antagonized the b inding of [H-3]CPX to the A(1)AR of rat brain with affinities similar to those of CPX; compound 8c was twice as potent as CPX. Analogues 8a, b and 13a were less potent than CPX, but for each the K-i of antagonis m was greater than or equal to 0.5 nM. Attempts to iodinate the 8-(4-h ydroxyphenyl) analogue of CPX failed, probably because the xanthine su bstituent strongly deactivated the phenol toward electrophilic iodinat ion. In summary, several of the modifications of the propyl groups of CPX needed to produce ligands for imaging by PET and SPET preserve or enhance affinity for the A(1)AR.