A novel method for the synthesis of carbon-14-labeled N-[3-(1-methyl-4-piperidinyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]propanamide and its use in quantitative whole-body autoradiography studies

• Published in: Journal of labelled compounds & radiopharmaceuticals 2005-08, Vol.48 (9), p.669-681
• Main Authors: Wheeler, William J., Chay, Sylvia H., Herman, Jennifer L., O'Bannon, Douglas D.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; carbon-14; Contrast media. Radiopharmaceuticals; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; QWBA; SSOFRA's
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.959

Sumitriptan (1), a non‐selective 5‐HT1B/1D agonist is an effective therapeutic agent for the acute treatment of migraine, but it is contraindicated for use in patients with known heart disease. The first Selective Serotonin One F Receptor Agonist (SSOFRA), 5‐(4′‐fluorobenz‐amido)‐3‐(N‐methyl‐piperidin‐4‐yl)‐1H‐indole (2) was demonstrated to be clinically useful in the treatment of migraine. Although 2 exhibited high affinity for the 5‐HT1F receptor as well as high selectivity for the 5‐HT1F receptor relative to 5‐HT1B and 5‐HT1D receptors, it demonstrated appreciable affinity for the 5‐HT1A receptor. Subsequently, a program was launched to discover SSOFRA's with improved selectivity over other 5‐HT1 receptor subtypes. As a result of these efforts, N‐[3‐(1‐methyl‐4‐piperidinyl)‐1H‐pyrrolo[3,2‐b]pyridin‐5‐yl]propanamide (3) was found to possess greater than 100‐fold selectivity over 5‐HT1A, 5‐HT1B and 5‐HT1D receptors. Pursuant to a potential clinical investigation of 3, its carbon‐14‐labeled isotopomer has been prepared by a circuitous route from unlabeled 3 and used in quantitative whole‐body autoradiography studies in rats. The results of these efforts are reported herein. Copyright © 2005 John Wiley & Sons, Ltd.