Synthesis of the serotonin transporter ligand (±)-10-methyl 3-[6-nitro-(2-quinolinyl)]-3,10-diazabicyclo-[4.3.1]-decane ([11C-methyl]NS 2495) and first in vivo results

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 46; no. 9; pp. 873 - 882
• Main Authors: Audrain, Hélène, Bender, Dirk, Scheel-Krüger, Jørgen, Nielsen, Elsebet Ø., Olsen, Gunnar M., Peters, Dan, Cumming, Paul
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2003; Wiley
• Subjects: 11C-methylation; Biological and medical sciences; Contrast media. Radiopharmaceuticals; Medical sciences; PET; Pharmacology. Drug treatments; radiolabelling; selective serotonin reuptake inhibitor; Nitro compound; Membrane protein; Intravenous administration; Nitrogen heterocycle; Ligand; Central nervous system; Carbon Isotopes; Reuptake inhibitor; Tissue; Scintigraphic agent; Bicyclic compound; Aromatic compound; Chemical synthesis; Carbon 14; Ungulata; Carrier protein; Radiolabelling; Serotonin; Pig; Vertebrata; Mammalia; Animal; Distribution; Artiodactyla; Iodomethane; Methylation; Pharmacokinetics; Positron emission tomography; Brain (vertebrata)
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.726

The serotonin transporter ligand (±)‐10‐[11C]‐methyl 3‐[6‐nitro‐(2‐quinolinyl)]‐3,10‐diazabicyclo‐[4.3.1]‐decane ([11C‐methyl]NS 2495) was synthesized via a methylation reaction with [11C]methyl iodide. The radiochemical purity exceeded 99% and the specific radioactivity was found to be 1.8 GBq/μmol at 40 min after the end of bombardment. The uptake of the tracer in the brain of a living pig was recorded by positron emission tomography (PET), first in a baseline condition, and again after treatment with citalopram (1 mg/kg, i.v.) to displace the specific binding. The distribution volume relative to the metabolism‐corrected arterial input was high in pig brain, ranging from 75–150 ml g−1; treatment with citalopram uniformly reduced the distribution volume to 75 ml g−1. Binding potential (pB) maps generated using the cerebellum as a reference tissue showed highest binding in the mesencephalon and cingulate cortex, where the magnitude of pB was close to 0.6. Thus, the pattern of binding in vivo agrees with the known pattern of serotonin innervations in pig brain. However, the specific binding was incompletely displaced by pre‐treatment with citalopram. Thus, [11C‐methyl]NS 2495 can label serotonin transporters in a PET study of the brain of a living pig, but full displacement by cold citalopram was not obtained in vivo, possibly reflecting binding sites which are inaccessible to citalopram. Copyright © 2003 John Wiley & Sons, Ltd.