Imaging Cortical Dopamine D1 Receptors Using [11C]NNC112 and Ketanserin Blockade of the 5-HT2A Receptors

Abstract

[11C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D1 receptor (R) over the 5-HT2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D1 R in the cortex. [11C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [11C]NNC112 in vivo D1 R selectivity, and (2) develop a feasible methodology for imaging cortical D1 R without contamination by 5-HT2A R. Seven healthy volunteers underwent [11C]NNC112 PET scans at baseline and after a 5-HT2A R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BPND change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BPND in the cortical (∼30%) and limbic regions (∼20%) but not in the striatum, which contains a much lower amount of 5-HT2A R. Therefore, ketanserin allows D1 R signal to be detected by [11C]NNC112 PET without significant 5-HT2A R contamination. These data confirm the presence of a significant 5-HT2A R contribution to cortical [11C]NNC112 signal, and call for caution in the interpretation of published [11C]NNC112 PET findings on cortical D1 R in humans. In the absence of more selective ligands, [11C]NNC112 PET with ketanserin can be used for cortical D1 R imaging in vivo.