MAPPING CATECHOL-O-METHYLTRANSFERASE IN-VIVO - INITIAL STUDIES WITH [F-18] RO41-0960

Ro41-0960 is a potent, fluorine containing COMT inhibitor which has be en reported to cross the blood brain barrier and to inhibit COMT in th e brain. It is structurally similar to Ro40-7592 which is currently un dergoing clinical trials in Parkinson's disease. Positron emission tom ographic (PET) studies in baboon using F-18 labeled Ro41-0960 demonstr ated a negligible uptake in the brain both at tracer doses and with th e addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The brain to plasma ratios of F-18 averaged ab out 0.025. Region of interest analysis of the brain tissue area sugges ts that most of F-18 in the brain was due to the blood in the brain an d not the brain tissue itself. However, high uptake was observed in th e kidneys and in other organs which are known to have high COMT activi ty. Studies in mice showed that at 30 min after injection of tracer, F -18 in kidneys was largely as unchanged [18F]Ro41-0960 and that it cou ld be displaced with unlabeled Ro41-0960. The fact that the average br ain to blood ratio for mice (n=12) was 0.04, and that similar HPLC met abolite patterns were observed for brain and blood, provides consisten t evidence that nearly all the F-18 in the brain repre-sents F-18 in t he cerebral blood vessels. These studies raise the question of whether the central pharmacological effects of Ro41-0960 are due to its prese nce in the brain. They also provide the first example of a positron em itter labeled radiotracer for COMT, and provide initial encouraging ev idence that [18F]Ro41-0960 may be used to examine COMT in peripheral o rgans in vivo.