Quantifying drug-related 5-HT1A receptor occupancy with [F-18]MPPF

Rationale: There is an increased interest in measuring the interaction of new or established drugs with their targets, in order to gain a better understanding of their mechanisms of action. PET can provide this information if an appropriate radioligand is available. [F-18]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[F-18]fluorobenzamido]ethylpiperazine) is a selective radioligand for serotonin 5-HT1A receptors. We have established that the binding potential (BP=B-max/K-D) of [F-18]MPPF for cerebral 5-HT1A receptors can be assessed in human brain without arterial sampling. Objectives: The aim of this study was to assess if 5-HT1A receptor occupancy can be measured through calculation of a drug-related decrease in BP with [F-18]MPPF and PET. Methods: Six volunteers were scanned twice using a Siemens Exact HR+ camera following injection of 70+/-18 MBq [F-18]MPPF (baseline and medicated conditions). Before the second scan, volunteers orally received either 3x10 mg pindolol at T=-15.5 h, T=-6.5 h, and T=-1.5 h (n=3) or 10 mg buspirone in a single dose at T=-1.5 h (n=3). Binding potentials were calculated using the simplified reference tissue model with the cerebellum as reference. Results: Administration of 30 mg pindolol led to a significant reduction in [F-18]MPPF binding potential of 42+/-17%. In contrast, no significant reduction of [F-18]MPPF binding potential was observed following administration of buspirone (5+/-17%). Conclusions: These results show that [F-18]MPPF can be used for measurement of drug-related 5-HT1A receptor occupancy and may be of particular interest in determining the 5-HT1A receptor interaction of new or established drugs in phase 1 and early phase 2 drug trials. Apparently, the 5-HT1A partial agonist buspirone is already clinically effective at low levels of 5-HT1A receptor occupancy