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Article

Synthesis and Biological Evaluation of the Mitochondrial Complex 1 Inhibitor 2-[4-(4-Fluorobutyl)benzylsulfanyl]-3-methylchromene-4-one as a Potential Cardiac Positron Emission Tomography Tracer

Heike Radeke,* Kelley Hanson, Padmaja Yalamanchili, Megan Hayes, Zhi-Qin Zhang, Michael Azure, Ming Yu, Mary Guaraldi, Mikhail Kagan, Simon Robinson, and David Casebier

Research and Development, Bristol-Myers Squibb Medical Imaging, 331 Treble Cove Road, North Billerica, Massachusetts 01862

J. Med. Chem., 2007, 50 (18), pp 4304–4315

DOI: 10.1021/jm0701831

Publication Date (Web): August 15, 2007

Corresponding author. Phone: (978) 671-8151. Fax: (978) 436-7500. E-mail: heike.radeke@bms.com.

Abstract

A series of fluorinated chromone analogs with IC₅₀ values ranging from 9 to 133 nM for the mitochondrial complex 1 (MC-I) has been prepared. A structure−activity relationship (SAR) study of the most potent fluorinated chromone analog 10 demonstrated the linkage heteroatom preference of the side chain region of the molecule while maintaining potent MC-I inhibitory activity. Tissue distribution studies 30 min after [¹⁸F]10 administration to Sprague−Dawley (SD) rats demonstrated high uptake of the radiotracer from the blood pool into the myocardium (2.24% ID/g), kidney (1.93% ID/g), and liver (2.00% ID/g). After 2 h about 66% of the activity in the myocardium at 30 min had been retained, whereas 70% had been cleared from the liver and kidney. MicroPET images of SD rats after [¹⁸F]10 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.