Quantitative validation of an intracerebral β-sensitive microprobe system to determine in vivo drug-induced receptor occupancy using [11C]raclopride in rats

In this study, we evaluated the potential of using a new beta-sensitive microprobe system for in vivo quantification of [C-11]raclopride binding and for in vivo determination of drug-induced receptor occupancy in the rat striatum. To validate this system, an ex vivo tissue dissection method was used to corroborate in vivo beta-microprobe measurements. Our data showed that the beta-microprobe-derived [C-11]raclopride binding kinetics in striatum could be quantified using a tissue compartmental model with a cerebellar reference region. Haloperidol (0.001-0.1 mg/kg; i.v.) induced a dose-dependent decrease in [C-11]raclopride binding in striatum as measured using the beta-microprobe with an ED50 value of 0.013 mg/kg. Highly significant relationships (P < 0.0001) were observed, within the same animals, between in vivo and ex vivo measures of haloperidol-induced D-2-receptor occupancy (r = 0.98) as well as between in vivo and ex vivo measures of [C-11]raclopride binding potentials (r = 0.99). Results from pretreatment and displacement studies with unlabeled raclopride and amphetamine conformed to the effect of these drugs as observed in humans using [C-11]raclopride and PET and allowed estimation of the in vivo k(off) value of raclopride to 0.025 +/- 0.004 min. However, allowing the system to stabilize before measurements and shielding the photomultiplier tubes were critical for obtaining these consistent results. This study demonstrates that the beta-microprobe provides reliable measurements of [C-11]raclopride binding kinetics in rodents, allows for quantitative in vivo measurements of antipsychotic drug action in brain, and represents a valid and cost-effective alternative to positron emission tomography imaging in small animals.