title: Carbon-14 radiolabeling and in vivo biodistribution of a potential anti-TB compound.
abstract: A potential anti-TB compound bearing a nitroimidazole moiety from iThemba Pharmaceuticals TB chemical library exhibits promising in vitro activity in the microplate almar blue assay (MABA) with a minimum inhibitory concentration (MIC) value of 3 µg/mL. It is equipotent to the front-line drug Isoniazid, but the compound is less toxic with an IC50 of >100 µg/mL. Therefore, this potential iThemba nitroimidazole, 4-([1,1'-[(14)C6]biphenyl]-4-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1,3,6]oxadiazocine, was radiolabeled with the C-14 isotope. The synthesis of the (14)C-labeled nitroimidazole was accomplished in seven steps from diethanolamine with a final specific radioactivity of 3.552 GBq/mmol, a radiochemical yield of 87%, and a radiochemical purity of ≥96%. The source of the C-14 radiolabel was bromobenzene which was introduced by the Suzuki-Miyaura reaction. Tissue distribution results showed that the radiotracer has a high accumulation in the lungs of TB-infected mice, statistically significantly higher than in healthy mice. However, the clearance (for both TB-infected and non-TB-infected mice) from all organs (except the small intestine) from 1 to 2 h as well as the low percentage of injected dose per gram values achieved indicates breakdown of the compound in vivo and subsequent clearance from the body. The latter suggests that the compound might not be useful as an anti-TB drug in humans.
authors.affiliation: Necsa, Radiochemistry, P. O. Box 482, Pretoria, 0001, South Africa.
authors.forename: Molahlehi S
authors.initials: MS
authors.lastname: Sonopo
authors.forename: Kobus
authors.initials: K
authors.lastname: Venter
authors.forename: Grant
authors.initials: G
authors.lastname: Boyle
authors.forename: Susan
authors.initials: S
authors.lastname: Winks
authors.forename: Biljana
authors.initials: B
authors.lastname: Marjanovic-Painter
authors.forename: Jan R
authors.initials: JR
authors.lastname: Zeevaart
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes / Q000737:chemistry; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D009593:Nitroimidazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000995:Antitubercular Agents; D002250:Carbon Radioisotopes; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals
keywords: C-14 labeling; TB research; nitroimidazole