title: Multiinjection approach for D2 receptor binding quantification in living rats using [11C]raclopride and the beta-microprobe: crossvalidation with in vitro binding data.
abstract: The purpose of this study was to quantify D2 receptors density and affinity in living rats using [11C]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) [11C]raclopride catabolism evaluation without and with cimetidine pretreatment (cytochrome P450 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) D2 striatal B'max and KdVr estimates obtained by compartmental modelling were 19.87+/-6.45 and 6.2+/-3.3 nmol/L, respectively. Cerebellum is the best candidate as a reference region with no specific binding detectable in vivo. (iii) When comparing density (Bmax/B'max) and affinity (Kd/KdVr) values in vivo and in vitro for each striatum, a high strict correlation was found (r2=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 D2-receptor density and affinity, in the living rodent striatum.
authors.affiliation: Unité de Recherche Associée Commissariat á l'Energie Atomique-Centre National de La Recherche Scientifique, Orsay, France. mauger@shfj.cea.fr
authors.forename: Gweltas
authors.initials: G
authors.lastname: Mauger
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dolle
authors.forename: Christine
authors.initials: C
authors.lastname: Coulon
authors.forename: Yann
authors.initials: Y
authors.lastname: Bramoullé
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Grégoire
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002250:Carbon Radioisotopes / Q000008:administration & dosage / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002927:Cimetidine / Q000008:administration & dosage; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D008297:Male; D015335:Molecular Probes / Q000008:administration & dosage / Q000378:metabolism*; D009924:Organ Culture Techniques; D011485:Protein Binding; D020891:Raclopride / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D015335:Molecular Probes; D017448:Receptors, Dopamine D2; D020891:Raclopride; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System