[O-methyl-(11)C]N-(4-(4-(3-Chloro-2-methoxyphenyl)-piperazin-1-yl)butyl)-1H-indole-2-carboxamide ([(11)C]BAK4-51) Is an Efflux Transporter Substrate and Ineffective for PET Imaging of Brain D(3) Receptors in Rodents and Monkey

Selective high-affinity antagonists for the dopamine D(3) receptor (D(3)R) are sought for treating substance use disorders. Positron emission tomography (PET) with an effective D(3)R radioligand could be a useful tool for the development of such therapeutics by elucidating pharmacological specificity and target engagement in vivo. Currently, a D(3)R-selective radioligand does not exist. The D(3)R ligand, N-(4-(4-(3-chloro-2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indole-2-carboxamide (BAK4-51, 1), has attractive properties for PET radioligand development, including full antagonist activity, very high D(3)R affinity, D(3)R selectivity, and moderate lipophilicity. We labeled 1 with the positron-emitter carbon-11 (t(1/2) = 20.4 min) in the methoxy group for evaluation as a radioligand in animals with PET. However, [(11)C]1 was found to be an avid substrate for brain efflux transporters and lacked D(3)R-specific signal in rodent and monkey brain in vivo.