[ O- methyl-11C] N-(4-(4-(3-Chloro-2-methoxyphenyl)-piperazin-1-yl)butyl)-1 H-indole-2-carboxamide ([11C]BAK4-51) Is an Efflux Transporter Substrate and Ineffective for PET Imaging of Brain D₃ 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

doi:10.3390/molecules23112737

[ O- methyl-¹¹C] N-(4-(4-(3-Chloro-2-methoxyphenyl)-piperazin-1-yl)butyl)-1 H-indole-2-carboxamide ([¹¹C]BAK4-51) Is an Efflux Transporter Substrate and Ineffective for PET Imaging of Brain D₃ Receptors in Rodents and Monkey

Molecules. 2018 Oct 23;23(11):2737. doi: 10.3390/molecules23112737.

Authors

Jeih-San Liow¹, Cheryl L Morse², Shuiyu Lu³, Michael Frankland⁴, George L Tye⁵, Sami S Zoghbi⁶, Robert L Gladding⁷, Anver B Shaik⁸, Robert B Innis⁹, Amy H Newman¹⁰, Victor W Pike¹¹

Affiliations

¹ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. liowj@mail.nih.gov.
² Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. morsec@mail.nih.gov.
³ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. shuiyu.lu@mail.nih.gov.
⁴ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. michael.frankland@nih.gov.
⁵ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. george.tye@gmail.com.
⁶ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. zoghbis@mail.nih.gov.
⁷ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. gladdingr@mail.nih.gov.
⁸ 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. aner.shaik@nih.gov.
⁹ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. innisr@mail.nih.gov.
¹⁰ 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. anewman@intra.nida.nih.gov.
¹¹ Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Room B3C346, 10 Center Drive, Bethesda, MD 20892, USA. pikev@mail.nih.gov.

Abstract

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 (t_1/2 = 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.

Keywords: PET; antagonist; dopamine D3 receptors; efflux transporter substrate; radiolabeling.

MeSH terms

Animals
Brain / diagnostic imaging*
Brain / metabolism*
Dopamine Agents / chemistry
Dopamine Agents / metabolism*
Haplorhini
Mice
Molecular Structure
Neuroimaging* / methods
Positron-Emission Tomography* / methods
Radiopharmaceuticals / chemistry
Radiopharmaceuticals / metabolism*
Rats
Receptors, Dopamine D3 / metabolism*
Rodentia

Substances

Dopamine Agents
Radiopharmaceuticals
Receptors, Dopamine D3

Grants and funding

ZIA-MH002793, ZIA-MH002795, ZIA-DA000424/National Institutes of Health