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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

  • J. S. Dileep Kumar
  • Jaya Prabhakaran
  • Vattoly J. Majo
  • Matthew S. Milak
  • Shu-Chi Hsiung
  • Hadassah Tamir
  • Norman R. Simpson
  • Ronald L. Van Heertum
  • J. John Mann
  • Ramin V. Parsey
Original Article

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.

Keywords

Brain Imaging Nuclear medicine PET Radiopharmaceuticals 

Notes

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • J. S. Dileep Kumar
    • 1
    • 2
  • Jaya Prabhakaran
    • 1
  • Vattoly J. Majo
    • 1
  • Matthew S. Milak
    • 1
  • Shu-Chi Hsiung
    • 1
  • Hadassah Tamir
    • 1
  • Norman R. Simpson
    • 3
  • Ronald L. Van Heertum
    • 2
    • 3
  • J. John Mann
    • 1
    • 2
    • 3
  • Ramin V. Parsey
    • 1
    • 2
  1. 1.Department of PsychiatryColumbia University College of Physicians and SurgeonsNew YorkUSA
  2. 2.Division of Brain Imaging, Department of NeuroscienceNew York State Psychiatric InstituteNew YorkUSA
  3. 3.Department of RadiologyColumbia University College of Physicians and SurgeonsNew YorkUSA

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