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

Rationale: There is an increased interest in measuring the interaction of n ew or established drugs with their targets, in order to gain a better under standing 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 select ive radioligand for serotonin 5-HT1A receptors. We have established that th e binding potential (BP=B-max/K-D) of [F-18]MPPF for cerebral 5-HT1A recept ors can be assessed in human brain without arterial sampling. Objectives: T he aim of this study was to assess if 5-HT1A receptor occupancy can be meas ured through calculation of a drug-related decrease in BP with [F-18]MPPF a nd PET. Methods: Six volunteers were scanned twice using a Siemens Exact HR + camera following injection of 70+/-18 MBq [F-18]MPPF (baseline and medica ted 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 buspir one 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 referenc e. Results: Administration of 30 mg pindolol led to a significant reduction in [F-18]MPPF binding potential of 42+/-17%. In contrast, no significant r eduction of [F-18]MPPF binding potential was observed following administrat ion 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 interactio n of new or established drugs in phase 1 and early phase 2 drug trials. App arently, the 5-HT1A partial agonist buspirone is already clinically effecti ve at low levels of 5-HT1A receptor occupancy.