Carbon-11 PB-12:: An attempt to visualize the dopamine D4 receptor in the primate brain with positron emission tomography

The dopamine D-4 receptor (D4R) is expressed in low density in various extrastriatal brain regions. This receptor subtype is discussed in relation to the pathophysiology and treatment of schizophrenia but no selective positron emission tomography (PET) ligand is available to date to study the distribution in vivo. The arylpiperazine derivative N-[2-[4-(4-chlorophenyl)piperazin-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 performance liquid chromatography (HPLC) purification was about 35 min, The specific 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 widespread distribution of radioactivity in the brain, including the neocortex and thalamus. About 40% of total radioactivity in plasma represented unchanged radioligand at 60 min after injection as determined by HPLC. Pretreatment with the D4R ligand 3-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-1H-pyrollo[2,3-b]pyridine (L-745,870) prior to radioligand injection failed to demonstrate receptor specific binding in the monkey brain. Furthermore, the brain radioactivity distribution was left unaffected by pretreating with unlabeled PB-12. This failure to detect a D4R-specific signal may be related to a very low density of the D4R in primate brain, insufficient binding affinity of the radioligand, and a high background of nonspecific binding. It can be concluded from these findings that [C-11]PB-12 is not suitable to Visualize the D4R in the primate brain with PET. NUCL MED BIOL 27;8:707-714, 2000. (C) 2000 Elsevier Science Inc. All rights reserved.