C-Labeled pyrazinamide

Pyrazinamide (PZA) is a prodrug used in the treatment of (MTB) infection. PZA is converted to its active form, pyrazinoic acid, by the pyrazinamidase of MTB at the acidic site of infection. Pyrazinoic acid inhibits the type 1 fatty acid synthases of the bacilli. Accumulation of pyrazinoic acid is also thought to disrupt the membrane potential and interfere with the energy production necessary for survival of MTB. Mutations of the pyrazinamidase gene are responsible for the development of PZA resistance. PZA is largely bacteriostatic. PZA labeled with C ([C]PZA) has been generated by Liu et al. for and real-time analysis of the PZA pharmacokinetics (PK) and biodistribution with positron emission tomography (PET) (1). The half-life of C is 20.4 min. 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 (2, 3). 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 (4-6). 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 (7, 8). 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 ; 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 (2, 4, 5). The current treatment regime for drug-sensitive TB involves the use of rifampicin (RIF), isoniazid (INH), PZA, and ethambutol or streptomycin for two months, followed by four months of continued dosing with INH and RIF (9, 10). 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. [C]PZA can easily penetrate the BBB (PZA > INH > RIF); however, the PZA concentrations in the cerebrospinal fluid and brain were only slightly higher than its minimum inhibitory concentration (MIC) value against TB. This chapter summarizes the data obtained by Liu et al. regarding [C]PZA. The data obtained with regard to [C]RIF and [C]INH are described in the MICAD chapters on [C]RIF and [C]INH, respectively.