Imaging cortical dopamine D1 receptors using [11C]NNC112 and ketanserin blockade of the 5-HT2A receptors

[C-11]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 D-1 receptor (R) over the 5-HT2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D-1 R in the cortex. [C-11]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [C-11]NNC112 in vivo D-1 R selectivity, and (2) develop a feasible methodology for imaging cortical D-1 R without contamination by 5-HT2A R. Seven healthy volunteers underwent [C-11]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 (similar to 30%) and limbic regions (similar to 20%) but not in the striatum, which contains a much lower amount of 5-HT2A R. Therefore, ketanserin allows D-1 R signal to be detected by [C-11]NNC112 PET without significant 5-HT2A R contamination. These data confirm the presence of a significant 5-HT2A R contribution to cortical [C-11]NNC112 signal, and call for caution in the interpretation of published [C-11]NNC112 PET findings on cortical D-1 R in humans. In the absence of more selective ligands, [C-11]NNC112 PET with ketanserin can be used for cortical D-1 R imaging in vivo. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 985-993; doi:10.1038/jcbfm.2009.269; published online 23 December 2009