NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

Show details

11C-Labeled rifampicin

[11C]RIF
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: September 1, 2010.

Chemical name:11C-Labeled rifampicinImage RIF11C.jpg
Abbreviated name:[11C]RIF
Synonym:11C-Labeled rifampin
Agent Category:Compounds
Target:DNA-dependent RNA polymerase in bacterial cells
Target Category:Enzymes (bacteria)
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Non-human primates
Structure of [11C]RIF by Liu et al (1). Click on the PubChem for additional information.

Background

[PubMed]

Rifampicin (RIF) (or rifampin) is a rifamycin derivative with a clinically effective group of 4-methyl-1-piperazinaminyl. RIF is typically used to treat Mycobacterium infections, including tuberculosis (TB) (1, 2). By binding the β subunit, RIF inhibits the DNA-dependent RNA polymerase and thus prevents RNA and protein synthesis in bacterial cells (2, 3). RIF labeled with 11C ([11C]RIF) has been generated by Liu et al. for in vivo and real-time analysis of the RIF pharmacokinetics (PK) and biodistribution with positron emission tomography (PET) (1). The half-life of 11C 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 in vivo 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 11C or with 18F 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 RIF, isoniazid (INH), pyrazinamide (PZA), and ethambutol or streptomycin for two months, followed by four months of continued dosing with INH and RIF (2, 3). This regime is primarily based on PK studies in serum and 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 11C and investigated their PK and biodistribution in baboons with PET (1). Liu et al. found that the organ distribution and BBB penetration of each drug differed greatly. For [11C]RIF, its ability to penetrate the BBB was lower than that of PZA and INH (PZA > INH). The RIF concentrations in the lungs and brain were 10 times and 3−4 times higher, respectively, than the RIF minimum inhibitory concentration (MIC) value against TB, supporting the use of RIF for treating TB infections in the lungs and the central nervous system. This chapter summarizes the data of [11C]RIF obtained by Liu et al. The data obtained with [11C]INH and [11C]PZA were described in the MICAD chapters on [11C]INH and [11C]PZA, respectively.

Synthesis

[PubMed]

Liu et al. first synthesized the demethyl RIF (RIF precursor) and generated the [11C]CH3I from [11C]CO2 (1). Radiolabeling of the RIF piperazine moiety with [11C]CH3I was then accomplished with potassium carbonate and the combination of dimethyl sulfoxide and MeCN. The labeled product was subsequently purified, and ascorbic acid was added to prevent oxidation. The average decay-corrected yield of [11C]RIF, calculated from [11C]CH3I, was 15−25% with a total synthesis time of 50 min. [11C]RIF was >99% radiochemically pure with a specific activity of 21.46 GBq/µmol (580 mCi/μmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The lipophilicity (logD) of [11C]RIF was measured on the basis of octanol−water partitioning. The plasma protein binding (% of free fraction in plasma) of [11C]RIF was determined after incubation with baboon plasma for 10 min at room temperature. The logD was 1.67 and the plasma protein binding was 27.32%, which are similar to literature values reported elsewhere (1).

Animal Studies

Rodents

[PubMed]

No references are currently available.

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

Liu et al. studied the biodistribution of [11C]RIF in healthy baboons (n = 4) with PET imaging (1). The RIF concentrations in the brain and other organs were estimated on the basis of the weight of the baboon (17 kg), a standard drug dose (20 mg/kg), and the assumption that the positron signal derives primarily from the intact drug. Studies showed that the penetrating ability of [11C]RIF and/or its radiolabeled metabolites through the BBB was weaker than that of PZA and INH. The RIF concentration in the brain tissue was higher than in the cerebrospinal fluid. The concentration in the whole brain was 0.000642% injected dose per cubic centimeter (ID/cc) (1.09 μg/ml) at 30 min, 0.000536% ID/cc (0.912 μg/ml) at 60 min, and 0.000710% ID/cc (1.21 μg/ml) at 90 min after injection, which was three to four times higher than its MIC against TB. The detailed data about the [11C]RIF distribution in other organs were presented in table 2 in the paper published by Liu et al. In general, [11C]RIF showed a moderate distribution in the heart, lungs, and kidneys, and was then concentrated in the liver and gallbladder. In most organs, the RIF concentration exceeded that observed in plasma over the 90-min period except for the cortex of kidney at 60 min. The RIF concentration in the lungs was >10 times higher than its MIC. Liu et al. concluded that the RIF concentrations determined by imaging the distribution of [11C]RIF in healthy baboons were similar to those observed previously in mice, monkeys, and human, while PET imaging provided dynamic data from 0 min to 90 min. The PET imaging results supported the use of RIF for treating TB infections in the lungs and brain (1).

Human Studies

[PubMed]

No references are currently available.

References

1.
Liu L., Xu Y., Shea C., Fowler J.S., Hooker J.M., Tonge P.J. Radiosynthesis and bioimaging of the tuberculosis chemotherapeutics isoniazid, rifampicin and pyrazinamide in baboons. J Med Chem. 2010;53(7):2882–91. [PMC free article: PMC2866172] [PubMed: 20205479]
2.
Aristoff P.A., Garcia G.A., Kirchhoff P.D., Hollis Showalter H.D. Rifamycins--obstacles and opportunities. Tuberculosis (Edinb) 2010;90(2):94–118. [PubMed: 20236863]
3.
Tomioka H. Current status of some antituberculosis drugs and the development of new antituberculous agents with special reference to their in vitro and in vivo antimicrobial activities. Curr Pharm Des. 2006;12(31):4047–70. [PubMed: 17100611]
4.
Fox G.B., Chin C.L., Luo F., Day M., Cox B.F. Translational neuroimaging of the CNS: novel pathways to drug development. Mol Interv. 2009;9(6):302–13. [PubMed: 20048136]
5.
Komoda F., Suzuki A., Yanagisawa K., Inoue T. Bibliometric study of radiation application on microdose useful for new drug development. Ann Nucl Med. 2009;23(10):829–41. [PubMed: 19862482]
6.
Hammond L.A., Denis L., Salman U., Jerabek P., Thomas C.R. Jr, Kuhn J.G. Positron emission tomography (PET): expanding the horizons of oncology drug development. Invest New Drugs. 2003;21(3):309–40. [PubMed: 14578681]
7.
Lancelot, S. and L. Zimmer, Small-animal positron emission tomography as a tool for neuropharmacology. Trends Pharmacol Sci, 2010. [PubMed: 20599282]
8.
Lee C.M., Farde L. Using positron emission tomography to facilitate CNS drug development. Trends Pharmacol Sci. 2006;27(6):310–6. [PubMed: 16678917]
9.
Bauer M., Wagner C.C., Langer O. Microdosing studies in humans: the role of positron emission tomography. Drugs R D. 2008;9(2):73–81. [PubMed: 18298126]
10.
Wagner C.C., Muller M., Lappin G., Langer O. Positron emission tomography for use in microdosing studies. Curr Opin Drug Discov Devel. 2008;11(1):104–10. [PubMed: 18175273]

Views

Search MICAD

Limit my Search:


Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...