11C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 5; pp. 1053 - 1056
• Main Authors: Andersen, Valdemar L., Hansen, Hanne D., Herth, Matthias M., Dyssegaard, Agnete, Knudsen, Gitte M., Kristensen, Jesper L.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2015; Elsevier
• Subjects: 5-HT2A receptor; Carbon-11; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; N-methylation; PET; Pharmacology & Pharmacy; Physical Sciences; Pimavanserin; Science & Technology; N-methylation; 5-HT2A receptor; Pimavanserin; Carbon-11; PET; SEROTONIN RECEPTORS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.01.017

[Display omitted] Pimavanserin is a selective serotonin 2A receptor (5-HT2AR) inverse agonist that has shown promise for treatment of psychotic symptoms in patients with Parkinson’s disease. Here, we detail the 11C-labeling and subsequently evaluate pimavanserin as a PET-radioligand in pigs. [11C]Pimavanserin was obtained by N-methylation of an appropriate precursor using [11C]MeOTf in acetone at 60°C giving radiochemical yields in the range of 1–1.7GBq (n=4). In Danish Landrace pigs the radio ligand readily entered the brain and displayed binding in the cortex in accordance with the distribution of 5-HT2ARs. However, this binding could not be blocked by either ketanserin or pimavanserin itself, indicating high nonspecific binding. The lack of displacement by the 5-HT2R antagonist and binding in the thalamus suggests that [11C]pimavanserin is not selective for the 5-HT2AR in pigs.