SYNTHESIS AND BIOLOGICAL EVALUATION OF [C-11] MK-912 AS AN ALPHA(2)-ADRENERGIC RECEPTOR RADIOLIGAND FOR PET STUDIES

In vitro studies showed that MK-912 ((2S, 12bS) zo[b]furo[2,3-a]quinol izine)-2,4'-pyrimidn-2'-one) is a potent alpha(2)-adrenergic receptor antagonist with high affinity (K-i = 0.42, 0.26 and 0.03 nM to alpha(2 A), alpha(2B) and alpha(2C), respectively) and high selectivity (alpha (2A)/alpha(1A) = 240; alpha(2A)/D-1 = 3600; alpha(2A)/D-2 = 3500; alph a(2A)/5-HT1 = 700; alpha(2A)/5-HT2 = 4100). The compound was labeled w ith C-11 and evaluated in rodents and monkey as a specific radioligand for studying alpha(2)-adrenergic receptors using PET. [C-11]MK-912 (2 ) was synthesized by methylation of its desmethyl precursor, L-668,929 (1), with [C-11]CH3I in (Bu3O)P = 0 at 85 degrees C for 8 min followe d by purification with HPLC in 18% yield in a synthesis time of 45 min from end of bombardment (EOB), The specific activity was 0.83-0.93 Ci /mu mol and the radiochemical purity was 97%. The initial uptake of [C -11]MK-912 in mouse brain, heart, lung, liver and kidney was high (5%, 4%, 5%, 17% and 8% per gram of organ, respectively, at 5 min postinje ction) and the activities were then slowly cleared from these organs. The uptake of [C-11]MK-912 in rat olfactory tubercle, a brain region w ith high density of alpha(2)-adrenergic receptors, was reduced by 30%, and the ratio of radioactivity in olfactory tubercle/cerebellum was r educed from 2:1 to 1:1 by coinjection of [C-11]MK-912 with a potent al pha(2)-adrenergic receptor antagonist, atipamezole (3 mg/kg), indicati ng that compound 2 binds to alpha(2)-adrenergic receptors. However, a PET study in a rhesus monkey revealed that the initial influx of [C-11 ]MK-912 into various brain regions (cerebellum, cortex, olfactory tube rcle and striatum) was high (0.02%/cc), and the radioactivity was then washed out slowly and without significantly differential retention in these brain regions. This, coupled with the fact that none of the hig h density alpha(2)-adrenergic receptor brain regions exceeds a few mil limeters in diameter, suggests that [C-11]MK-912 is probably not an id eal radioligand for studying alpha(2)-adrenergic receptors in humans u sing commercially available PET. (C) 1998 Elsevier Science Inc.