Imaging the distribution of Carbon-11 labeled rifampicin, isoniazid and pyrazinamide in baboons using PET

1517 Objectives Use positron emission tomography (PET)to determine the brain and organ distribution of front-line tuberculosis chemotherapeutics isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) in baboons. Methods PET imaging studies were performed with [11C]RIF, [11C]INH and [11C]PZA to determine brain and organ distribution. Time-activity curves (TAC) were generated from the image data, which was acquired for 90 min following intravenous administration of each radiolabeled drug. Regions-of-interest (ROIs) were drawn manually. Results Radiosynthesis of each C-11 drug has been accomplished in 1 h, using 11CH3I to label RIF, and H11CN to label INH and PZA. Following i.v. administration, INH, PZA, RIF and/or their radiolabeled metabolites clear rapidly from many tissues, however INH, PZA and/or their metabolites accumulate in the bladder while RIF and/or its metabolites accumulates in the liver and gall bladder, consistent with the routes of excretion of the drugs. In addition, the biodistribution data demonstrate that the ability of the three drugs and their radiolabeled metabolites to cross the blood-brain barrier decreases in the order PZA > INH > RIF, although in all cases the estimated drug concentrations are greater than the MIC values for inhibiting bacterial growth. Conclusions The front-line TB chemotherapeutics INH, RIF and PZA have been labeled with carbon-11 and the biodistribution of the labeled drugs has been imaged in baboons in vivo. Estimates based on the weight of baboon, a standard drug dose and the assumption that the positron signal derives primarily from the intact drug indicates these drug are effective against TB and CNS TB. The PK and drug distribution data have important implications for treatment of disseminated TB in the brain, and set the scene for imaging the distribution of the pathogen in vivo. Research Support This work was supported by NIH grant AI084189 to PJT