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.
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 [(18)F]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 approximately 70% had been cleared from the liver and kidney. MicroPET images of SD rats after [(18)F]10 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.
Radeke
Heike
H
Research and Development, Bristol-Myers Squibb Medical Imaging, 331 Treble Cove Road, North Billerica, Massachusetts 01862, USA. heike.radeke@bms.com
Hanson
Kelley
K
Yalamanchili
Padmaja
P
Hayes
Megan
M
Zhang
Zhi-Qin
ZQ
Azure
Michael
M
Yu
Ming
M
Guaraldi
Mary
M
Kagan
Mikhail
M
Robinson
Simon
S
Casebier
David
D
D000818:Animals; D002417:Cattle; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005462:Fluorine Radioisotopes; D006321:Heart / Q000000981:diagnostic imaging*; D066298:In Vitro Techniques; D007553:Isotope Labeling; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013367:Submitochondrial Particles / Q000187:drug effects / Q000201:enzymology; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics; D014018:Tissue Distribution
C523903:2-(4-(4-fluorobutyl)benzylsulfanyl)-3-methylchromen-4-one; D002867:Chromones; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D013440:Sulfides; D017256:Technetium Tc 99m Sestamibi; D042967:Electron Transport Complex I