In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates

Authors

  • Jaya Prabhakaran Department of Psychiatry, Columbia University Medical Center, New York, USA. Area of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, USA.
  • Christine DeLorenzo Department of Psychiatry, Stony Brook University School of Medicine, Stony Brook, New York, USA.
  • Francesca Zanderigo Department of Psychiatry, Columbia University Medical Center, New York, USA. Area of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, USA.
  • Gitte M Knudsen Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen, Denmark.
  • Nic Gilling Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital Rigshospitalet, Denmark.
  • Mali Pratap Area of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, USA.
  • Matthew J Jorgensen Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
  • James Daunais Department of Physiology and Pharmacology, Wake Forest University Medical Center Winston-Salem, North Carolina, USA.
  • Jay R Kaplan Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
  • Ramin V Parsey Department of Psychiatry, Stony Brook University School of Medicine, Stony Brook, New York, USA.
  • J John Mann Department of Psychiatry, Columbia University Medical Center, New York, USA. Area of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, USA.
  • Dileep Kumar Area of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, USA.

DOI:

https://doi.org/10.18433/jpps30329

Abstract

Purpose: 5-HT2AR exists in high and low affinity states. Agonist PET tracers measure binding to the active high affinity site and thus provide a functionally relevant measure of the receptor. Limited in vivo data have been reported so far for a comparison of agonist versus antagonist tracers for 5-HT2AR used as a proof of principle for measurement of high and low affinity states of this receptor. We compared the in vivo binding of [11C]CIMBI-5, a 5-HT2AR agonist, and of the antagonist [11C]M100907, in monkeys and baboons. Methods: [11C]CIMBI-5 and [11C]M100907 baseline PET scans were performed in anesthetized male baboons (n=2) and male vervet monkeys (n=2) with an ECAT EXACT HR+ and GE 64-slice PET/CT Discovery VCT scanners. Blocking studies were performed in vervet monkeys by pretreatment with MDL100907 (0.5 mg/kg, i.v.) 60 minutes prior to the scan. Regional distribution volumes and binding potentials were calculated for each ROI using the likelihood estimation in graphical analysis and Logan plot, with either plasma input function or reference region as input, and simplified reference tissue model approaches. Results: PET imaging of [11C]CIMBI-5 in baboons and monkeys showed the highest binding in 5-HT2AR-rich cortical regions, while the lowest binding was observed in cerebellum, consistent with the expected distribution of 5-HT2AR. Very low free fractions and rapid metabolism were observed for [11C]CIMBI-5 in baboon plasma. Binding potential values for [11C]CIMBI-5 were 25-33% lower than those for [11C]MDL100907 in the considered brain regions. Conclusion: The lower binding potential of [11C]CIMBI-5 in comparison to [11C]MDL100907 is likely due to the preferential binding of the former to the high affinity site in vivo in contrast to the antagonist,  [11C]MDL100907, which binds to both high and low affinity sites.

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References

Philip H. Elsinga, PhD

Department of Nuclear Medicine and

Molecular Imaging, University Medical Center

Groningen, University of Groningen,

Groningen, The Netherlands

E-mail: p.h.elsinga@umcg.nl

Min-Jeong Kim, M.D., Ph.D. Molecular Imaging Branch,

National Institute of Mental Health

Center Drive, Bldg. 10, Rm B1D43 Bethesda, MD 20892-1026, USA

Tel: 301-451-8894

Fax: 301-480-3610

Email: min-jeong.kim@nih.gov

Dr. Jogesh Mukherji, PhD

Associate Professor, Department of Psychiatry & Human Behavior

Director of Radiopharmaceutical Development

Senior Chemist, Brain Imaging Center 162 Irvine Hall, University of California-Irvine, CA

E-mail: mukherjj@uci.edu

Neil Vasdev, Ph.D.

Director, Azrieli Centre for Neuro-Radiochemistry

Associate Director & Chief Radiochemist, Research Imaging Centre

Centre for Addiction and Mental Health

College St, Toronto, ON, M5T 1R8

Tel: 416-535-8501 ext. 30988; Email: neil.vasdev@utoronto.ca

Luc Zimmer

Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, INSERM, CNRS, 69500, Bron, France

CERMEP-Imaging Platform, 69677, Bron, France

Hospices Civils de Lyon, 69002, Lyon, France

zimmer@univ-lyon1.fr

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Published

2019-07-26

How to Cite

Prabhakaran, J., DeLorenzo, C., Zanderigo, F., Knudsen, G. M., Gilling, N., Pratap, M., … Kumar, D. (2019). In vivo PET Imaging of [11C]CIMBI-5, a 5-HT2AR Agonist Radiotracer in Nonhuman Primates. Journal of Pharmacy & Pharmaceutical Sciences, 22(1), 352–364. https://doi.org/10.18433/jpps30329

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Section

Pharmaceutical Sciences; Original Research Articles