[<i>O</i>-<i>methyl</i>-<sup>11</sup>C]<i>N</i>-(4-(4-(3-Chloro-2-methoxyphenyl)-piperazin-1-yl)butyl)-1<i>H</i>-indole-2-carboxamide ([<sup>11</sup>C]BAK4-51) Is an Efflux Transporter Substrate and Ineffective for PET Imaging of Brain D<sub>3</sub> Receptors in Rodents and Monkey
Jeih-San Liow,
Cheryl L. Morse,
Shuiyu Lu,
Michael Frankland,
George L. Tye,
Sami S. Zoghbi,
Robert L. Gladding,
Anver B. Shaik,
Robert B. Innis,
Amy H. Newman,
Victor W. Pike
Affiliations
Jeih-San Liow
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Cheryl L. Morse
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Shuiyu Lu
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Michael Frankland
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
George L. Tye
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Sami S. Zoghbi
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Robert L. Gladding
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Anver B. Shaik
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA
Robert B. Innis
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Amy H. Newman
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA
Victor W. Pike
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA
Selective high-affinity antagonists for the dopamine D3 receptor (D3R) are sought for treating substance use disorders. Positron emission tomography (PET) with an effective D3R radioligand could be a useful tool for the development of such therapeutics by elucidating pharmacological specificity and target engagement in vivo. Currently, a D3R-selective radioligand does not exist. The D3R 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 D3R affinity, D3R selectivity, and moderate lipophilicity. We labeled 1 with the positron-emitter carbon-11 (t1/2 = 20.4 min) in the methoxy group for evaluation as a radioligand in animals with PET. However, [11C]1 was found to be an avid substrate for brain efflux transporters and lacked D3R-specific signal in rodent and monkey brain in vivo.
