Multiinjection approach for D2 receptor bining quantification in living rats using [11C]raclopride and the β-microprobe:: crossvalidation with in vitro binding data

The purpose of this study was to quantify D-2 receptors density and affinity in living rats using [C-11]raclopride and to validate the multiinjection modelling approach. To this aim, we used an intracerebral beta(+)-sensitive probe as a highly sensitive system to quantify the radioligand activity using a single three-injection experimental paradigm. The study was divided into three main parts: (i) [C-11]raclopride catabolism evaluation without and with cimetidine pretreatment (cytochrome P-450 inhibitor); (ii) quantification of kinetics parameters in the striatum, enthorinal cortex, and cerebellum of living rats using a three-compartment model with an arterial input function; (iii) correlation study of in vivo and in vitro binding density and affinity values in the same striatal tissues. (i) raclopride catabolism was very reproducible between individuals; cimetidine pre-treatment resulted in a 30% reduction of raclopride metabolites. (ii) D-2 striatal B'(max). and KdVr estimates obtained by compartmental modelling were 19.87 +/- 6.45 and 6.2 +/- 3.3nmol/L, respectively. Cerebellum is the best candidate as a reference region with no specific binding detectable in vivo. (iii) When comparing density (B-max/B'(max)) and affinity (K-d/KdVr) values in vivo and in vitro for each striatum, a high strict correlation was found (r(2)=0.90 and 0.72, for density and affinity, respectively). These results validate the multi-injection modelling approach coupled to beta-microprobe acquisitions as a mean to provide accurate and separate estimates of dopamine D-2-receptor density and affinity, in the living rodent striatum.