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Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates

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Abstract

Purpose

Serotonin1A (5-HT1A) receptors exist in high- and low-affinity states, and agonist ligands bind preferentially to the high-affinity state of the receptor and provide a measure of functional 5-HT1A receptors. Although the antagonist tracers are established PET ligands in clinical studies, a successful 5-HT1A receptor agonist radiotracer in living brain has not been reported. [11C]MPT, our first-generation agonist radiotracer, shows in vivo specificity in baboons; however, its utility is limited owing to slow washout and immeasurable plasma free fraction. Hence we performed structure-activity relationship studies of MPT to optimize a radiotracer that will permit valid quantification of 5-HT1A receptor binding. We now report the synthesis and evaluation of [11C]MMP as an agonist PET tracer for 5-HT1A receptors in baboons.

Methods

In vitro binding assays were performed in bovine hippocampal membranes and membranes of CHO cells expressing 5-HT1A receptors. [11C] labeling of MMP was performed by reacting desmethyl-MMP with [11C]CH3OTf. In vivo studies were performed in baboons, and blocking studies were conducted by pretreatment with 5-HT1A receptor ligands WAY-100635 and (±)-8-OH-DPAT.

Results

MMP is a selective 5-HT1A receptor agonist (K i 0.15 nM). Radiosynthesis of [11C]MMP was achieved in 30 ± 5% (n = 15) yield at EOS with a specific activity of 2,600 ± 500 Ci/mmol (n = 12). PET studies in baboons demonstrated specific binding of [11C]MMP to 5-HT1A receptor-enriched brain regions, as confirmed by blockade with WAY-100635 and (±)-8-OH-DPAT.

Conclusion

We identified [11C]MMP as an optimal agonist PET tracer that shows quantifiable, specific binding in vivo to 5-HT1A receptors in baboons.

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Acknowledgement

This work was supported by research grants from the National Institute of Health (P50 MH62185, R21 MH077161 and K08 MH76258-01A1). The authors thank Dr. Bryan Roth and the NIMH-PDSP program for the competitive receptor-transporter binding assays. Ms. Agata Bukowska assisted in the radiolabeling studies.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, USA

    J. S. Dileep Kumar, Jaya Prabhakaran, Vattoly J. Majo, Matthew S. Milak, Shu-Chi Hsiung, Hadassah Tamir, J. John Mann & Ramin V. Parsey

  2. Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, New York, USA

    J. S. Dileep Kumar, Ronald L. Van Heertum, J. John Mann & Ramin V. Parsey

  3. Department of Radiology, Columbia University College of Physicians and Surgeons, New York, USA

    Norman R. Simpson, Ronald L. Van Heertum & J. John Mann

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  1. J. S. Dileep Kumar
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  2. Jaya Prabhakaran
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Correspondence to J. S. Dileep Kumar.

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Kumar, J.S.D., Prabhakaran, J., Majo, V.J. et al. Synthesis and in vivo evaluation of a novel 5-HT1A receptor agonist radioligand [O-methyl-11C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione in nonhuman primates. Eur J Nucl Med Mol Imaging 34, 1050–1060 (2007). https://doi.org/10.1007/s00259-006-0324-y

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