Carbon-11 PB-12: An attempt to visualize the dopamine D-4 receptor in the primate brain with positron emission tomography

The dopamine D-4 receptor (D4R) is expressed in low density in various extr astriatal brain regions. This receptor subtype is discussed in relation to the pathophysiology and treatment of schizophrenia but no selective positro n emission tomography (PET) ligand is available to date to study the distri bution in vivo. The arylpiperazine derivative N-[2-[4-(4-chlorophenyl)piper azin-1-yl]ethyl]-3-methoxybenzamide (PB-12) is a never, high affinity (K-i = 0.040 nM) and selective D4R ligand. We radiolabeled PB-12 with carbon-11 (t(1/2) 20.4 min) by O-methylation of the corresponding desmethyl analogue N-[2-[4-(4-chloro phenyl)piperazin-1-yl]ethyl]-3-hydroxybenzamide (LM-190) with [C-11]methyl triflate. Derivative LM-190 was prepared by condensing 3- hydroxybenzoic acid with the appropriate amine. For the radiolabeling, the incorporation yield was >90% and the total synthesis time including high pe rformance liquid chromatography (HPLC) purification was about 35 min, The s pecific radioactivity of [C-11]PB-12 at time of injection was 67-118 GBq . mu mol(-1). PET studies in a cynomolgus monkey showed a high uptake and wid espread distribution of radioactivity in the brain, including the neocortex and thalamus. About 40% of total radioactivity in plasma represented uncha nged radioligand at 60 min after injection as determined by HPLC. Pretreatm ent with the D4R ligand 3-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-1H-pyr ollo[2,3-b]pyridine (L-745,870) prior to radioligand injection failed to de monstrate receptor specific binding in the monkey brain. Furthermore, the b rain radioactivity distribution was left unaffected by pretreating with unl abeled PB-12. This failure to detect a D4R-specific signal may be related t o a very low density of the D4R in primate brain, insufficient binding affi nity of the radioligand, and a high background of nonspecific binding. It c an be concluded from these findings that [C-11]PB-12 is not suitable to Vis ualize the D4R in the primate brain with PET. NUCL MED BIOL 27;8:707-714, 2 000. (C) 2000 Elsevier Science Inc. All rights reserved.