C-Labeled isoniazid

Isoniazid, also known as isonicotinylhydrazine (INH), is a first-line drug used in the prevention and treatment of tuberculosis (TB) (1, 2). INH is a prodrug that is activated by the catalase-peroxidase enzyme KatG of the mycobacteria. The activation process leads to the formation of the isonicotinic acyl-NADH complex. Subsequent binding of the complex with the enoyl-acyl carrier protein reductase InhA results in the inhibition of mycolic acid synthesis, which is essential for the wall of mycobacteria (3). INH is bactericidal to rapidly dividing mycobacteria but is bacteriostatic to slow-growing mycobacteria. INH labeled with C ([C]INH) has been generated by Liu et al. for and real-time analysis of the INH pharmacokinetics (PK) and biodistribution with positron emission tomography (PET) (1). The half-life of C is 20.4 min, allowing for a ~60 min window to observe the PK. The PK and biodistribution of a novel drug are traditionally determined with blood and tissue sampling and/or autoradiography. Despite high workload and huge investment in drug development, only 8% of the drugs entering clinical trials today reach the market, as estimated by the U.S. Food and Drug Administration. One main reason for this attrition is insufficient exploration of the drug–target interaction (1). Traditional methods are inadequate to answer questions such as whether a drug reaches the target, how the drug interacts with its targets, and how the drug modifies the diseases. Because of the high resolution and sensitivity of newly developed imaging techniques, investigators have become increasingly interested in addressing these issues (4, 5). In the case of PET imaging, most small molecules can now be efficiently labeled with C or with F at >37 GBq/µmol (1 Ci/μmol), and they can be detected with PET in the nanomolar to picomolar concentration range (6-8). Consequently, a sufficient signal for imaging can be obtained even though the total amount of a radiotracer administered systemically is extremely low (known as microdosing, typically <1 μg for humans). Microdosing is particularly valuable for evaluating tissue exposure in the early phase of drug development when the full-range toxicology is not yet available (9, 10). Increasing evidence has demonstrated the efficiency of PET imaging in obtaining quantitative information on drug PK and distribution in various tissues including brain; confirming drug binding with targets and elucidating the relationship between occupancy and target expression/function in vivo; assessing drug passage across the blood–brain barrier (BBB) and ensuring sufficient exposure to brain for central nervous system drugs; and dissecting the modifying effects of drugs on diseases (4, 6, 7). The current treatment regime for drug-sensitive TB involves the use of rifampicin (RIF), INH, pyrazinamide (PZA), and ethambutol or streptomycin for two months, followed by four months of continued dosing with INH and RIF (11, 12). This regime is primarily based on PK studies in serum and on efficacy of treatment. The efficacy of each drug for different types of TB such as brain TB and the drug distribution in each compartment of an organ are not well understood. To provide direct insights into these drugs, Liu et al. labeled INH, RIF, and PZA with C and used PET to investigate their PK and biodistribution in baboons (1). Liu et al. found that the organ distribution and BBB penetration of each drug differed greatly. The ability of [C]INH to penetrate the BBB was lower than that of PZA but higher than that of RIF (PZA > INH > RIF). The INH concentrations in the lungs and brain were ten times higher than the INH minimum inhibitory concentration (MIC) value against TB, supporting the use of INH for treating TB infections in the lungs and brain. This chapter summarizes the data obtained by Liu et al. regarding [C]INH. The data obtained with regard to [C]RIF and [C]PZA are described in the MICAD chapters on [C]RIF and [C]PZA, respectively.