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Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

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Abstract

Purpose

Positron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [11C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT2A receptor agonist PET tracers in the pig brain.

Methods

Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT2A receptor binding, cortical nondisplaceable binding potentials (BPND) were calculated using the simplified reference tissue model with the cerebellum as a reference region.

Results

After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT2A receptor distribution. The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [11C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT2A receptor selectivity in vivo. [11C]Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND, while [11C]Cimbi-27, [11C]Cimbi-29, [11C]Cimbi-31 and [11C]Cimbi-88 gave rise to cortical BPND similar to that of [11C]Cimbi-5.

Conclusion

[11C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.

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Acknowledgments

The technical assistance of Letty Klarskov, Mette Værum Olesen, Bente Dall and Jack Frausing Nielsen is gratefully acknowledged. This study was financially supported by the Lundbeck Foundation, University of Copenhagen, Faculty of Health Sciences, the Toyota Foundation, the John and Birthe Meyer Foundation, and by the EU 6th Framework program DiMI (LSHB-CT-2005-512146). [3H]MDL100907 was kindly provided by Prof. Christer Halldin, Karolinska Institute, Sweden. K i determinations at neuroreceptors were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract no. HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth, MD PhD, at the University of North Carolina at Chapel Hill, and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA.

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Authors and Affiliations

  1. Neurobiology Research Unit, Copenhagen University Hospital, Blegdamsvej 9, Rigshospitalet, building 9201, DK-2100, Copenhagen, Denmark

    Anders Ettrup, Martin A. Santini, Mikael Palner & Gitte M. Knudsen

  2. PET and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Nic Gillings, Szabolcs Lehel, Matthias M. Herth & Jacob Madsen

  3. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark

    Martin Hansen, James Paine, Jesper Kristensen & Mikael Begtrup

  4. Center for Integrated Molecular Brain Imaging (Cimbi), Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    Anders Ettrup, Martin Hansen, Martin A. Santini, James Paine, Nic Gillings, Mikael Palner, Matthias M. Herth, Jacob Madsen, Jesper Kristensen, Mikael Begtrup & Gitte M. Knudsen

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  1. Anders Ettrup
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  2. Martin Hansen
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Correspondence to Gitte M. Knudsen.

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Ettrup, A., Hansen, M., Santini, M.A. et al. Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers. Eur J Nucl Med Mol Imaging 38, 681–693 (2011). https://doi.org/10.1007/s00259-010-1686-8

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