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Preclinical Safety Assessment of the 5-HT2A Receptor Agonist PET Radioligand [11C]Cimbi-36

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Abstract

Purpose

[11C]Cimbi-36 was recently developed as an agonist radioligand for brain imaging of serotonin 2A receptors (5-HT2A) with positron emission tomography (PET). This may be used to quantify the high-affinity state of 5-HT2A receptors and may have the potential to quantify changes in cerebral 5-HT levels in vivo. We here investigated safety aspects related to clinical use of [11C]Cimbi-36, including radiation dosimetry and in vivo pharmacology.

Procedures

[11C]Cimbi-36 was injected in rats or pigs, and radiation dosimetry was examined by ex vivo dissection or with PET scanning, respectively. Based on animal data, the Organ Level INternal Dose Assessment software was used to estimate extrapolated human dosimetry for [11C]Cimbi-36. The 5-HT2A receptor agonist actions of [11C]Cimbi-36 in vivo pharmacological effects in mice elicited by increasing doses of Cimbi-36 were assessed with the head-twitch response (HTR).

Results

The effective dose as extrapolated from both rat and pig data was low, 7.67 and 4.88 μSv/MBq, respectively. In addition, the estimated absorbed radiation dose to human target organs did not exceed safety levels. Administration of 0.5 mg/kg Cimbi-36 leads to significant HTR compared to saline, whereas 0.05 mg/kg Cimbi-36 (doses much larger than those given in conjunction with a PET scan) did not elicit a significant HTR.

Conclusions

Administration of tracer doses of [11C]Cimbi-36 does not seem to be associated with unusual radiation burden or adverse clinical effects.

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Acknowledgments

The technical assistance of Cecilia Ratner, Hanne Demant Hansen, Jahangeer Sakhi, Letty Klarskov, Mette Værum Olesen, Bente Dall, Lasse Kofoed Bech, and Agnete Dyssegaard is gratefully acknowledged. This study was financially supported by the Lundbeck Foundation, University of Copenhagen, Faculty of Health Sciences, the John and Birthe Meyer Foundation, the Aase and Ejner Danielsen Foundation, the Arvid Nilsson Foundation, and the EU 6th Framework program DiMI: (LSHB-CT-2005-512146).

Conflict of Interest

The authors declare that they have no conflict of interest.

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Correspondence to Gitte Moos Knudsen.

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Ettrup, A., Holm, S., Hansen, M. et al. Preclinical Safety Assessment of the 5-HT2A Receptor Agonist PET Radioligand [11C]Cimbi-36. Mol Imaging Biol 15, 376–383 (2013). https://doi.org/10.1007/s11307-012-0609-4

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