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Nucl Med Biol. 2019 Mar;70:1-13. doi: 10.1016/j.nucmedbio.2019.01.005. Epub 2019 Jan 26.

Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1B receptors.

Author information

1
Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-17176 Stockholm, Sweden; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1003, USA. Electronic address: anton.lindberg@ki.se.
2
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1003, USA.
3
Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-17176 Stockholm, Sweden.
4
Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-17176 Stockholm, Sweden; PET Science Centre, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, SE-17176 Stockholm, Sweden.
5
Isotope Chemistry, Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, SE-43250 Göteborg, Sweden.
6
Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892-5624, USA.

Abstract

INTRODUCTION:

The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT1B receptor binding in human brain has been examined with PET using radioligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radioligand may affect imaging performance, two high-affinity full 5-HT1B receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates.

METHODS:

[11C]4 was obtained through Pd(0)-mediated insertion of [11C]carbon monoxide between prepared iodoarene and homochiral amine precursors. [11C]5 was obtained through N-11C-methylation of N-desmethyl precursor 6 with [11C]methyl triflate. [11C]4 and [11C]5 were studied with PET in rhesus or cynomolgus monkey. [11C]4 was studied with PET in mice and rats to measure brain uptake and specific binding. Ex-vivo experiments in rats were performed to identify whether there were radiometabolites in brain. Physiochemical parameters for [11C]4 (pKa, logD and conformational energetics) were evaluated.

RESULTS:

Both [11C]4 and [11C]5 were successfully produced in high radiochemical purity and in adequate amounts for PET experiments. After intravenous injection of [11C]4, brain radioactivity peaked at a low level (0.2 SUV). Pretreatment with tariquidar, an inhibitor of the brain P-gp efflux transporter, increased brain exposure four-fold whereas pretreatment with a high pharmacological dose of the 5-HT1B antagonist, AR-A000002, had no effect on the binding. Ex-vivo experiments in rats showed no radiometabolites entering brain. [11C]5 also failed to enter monkey brain under baseline conditions.

CONCLUSIONS:

[11C]4 and [11C]5 show too low brain uptake and specific binding to be useful PET radioligands. Low brain uptake is partly ascribed to efflux transporter action as well as unfavorable conformations.

KEYWORDS:

Agonist; Carbon-11; Carbonylation; Radioligand; Serotonin subtype 1B receptor

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