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

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Abstract
In this study, we evaluated the potential of using a new β‐sensitive microprobe system for in vivo quantification of [11C]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 β‐microprobe measurements. Our data showed that the β‐microprobe‐derived [11C]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 [11C]raclopride binding in striatum as measured using the β‐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 D2‐receptor occupancy (r = 0.98) as well as between in vivo and ex vivo measures of [11C]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 [11C]raclopride and PET and allowed estimation of the in vivo koff value of raclopride to 0.025 ± 0.004 min−1. 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 β‐microprobe provides reliable measurements of [11C]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. Synapse 52:89–99, 2004.

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