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

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

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[18F]6-(2-Fluoropropyl)-4-methyl-pyridin-2-amine

[18F]iNOS-9
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: September 9, 2009.

Chemical name:[18F]6-(2-Fluoropropyl)-4-methyl-pyridin-2-amine
image 81058724 in the ncbi pubchem database
Abbreviated name:[18F]iNOS-9
Synonym:
Agent category:Compound
Target:Inducible nitric oxide synthase (iNOS)
Target category:Enzyme
Method of detection:Positron emission tomography (PET)
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Nitric oxide (NO) is produced as an important mediator in physiological and pathophysiological conditions by three isoforms of NO synthase (NOS): endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) (1, 2). NOSs are highly regulated for specific physiological roles in various tissues and cells. nNOS produces NO in neurons in both the central and peripheral nervous systems as a neurotransmitter and a neuronal modulator for cellular communication. NO is generated in blood vessels by eNOS in endothelial cells for blood pressure regulation. iNOS is induced by various inflammatory stimuli in activated macrophages and other types of cells and plays an important role in immunity and inflammation. iNOS is also essential for host defense against microorganisms and cancer cells.

The basal level of NO is usually very low. In contrast, activated iNOS can generate a large amount of NO over a prolonged period of time during acute and chronic inflammatory diseases (3). iNOS has been found to be overexpressed in a number of tumors compared with normal tissues (4). As a result of the involvement of iNOS in a variety of physiological processes in both normal and diseased states, it is necessary to develop a radiolabeled ligand for noninvasive measurement of iNOS expression. Zhou et al. (5) reported the development of a series of 2-amino-4-methylpyridine analogs as iNOS Inhibitors for positron emission tomography (PET) imaging for iNOS. One of them, [18F]6-(2-fluoropropyl)-4-methyl-pyridin-2-amine ([18F]iNOS-9), has been tested in mice.

Synthesis

[PubMed]

[18F]iNOS-9 was readily synthesized with standard 18F-fluorination of the N-BOC–protected mesylate precursor with ([18F]KF/Kryptofix2.2.2), followed by acid hydrolysis (5). The radiochemical yield was ~10% (decay-corrected) at the end of purification, and the specific activity was 80 ± 61 GBq/µmol (2.16 ± 1.66 Ci/µmol) at the end of synthesis. Radiochemical purity was >99% as determined with high-performance liquid chromatography. Total synthesis time was 120 min.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Zhou et al. (5) performed in vitro enzyme inhibition assays for iNOS, eNOS, and nNOS. iNOS-9 exhibited 50% inhibition concentration values of 220 ± 25 nM for iNOS, 1,500 ± 300 nM for eNOS, and 490 ± 80 nM for nNOS. [18F]iNOS-9 was 80% and 75% intact in rat blood at 37ºC for 1 h and 2 h, respectively.

Animal Studies

Rodents

[PubMed]

[18F]iNOS-9 (1.85 MBq (50 μCi)) was injected intravenously into normal and lipopolysaccharide (LPS)-treated mice (n = 4/group) to study the expression of iNOS induced by LPS (5). The organs with the highest accumulation in normal and LPS-treated groups at 60 min after injection were the liver (2.59 and 2.63% injected dose (ID)/g, respectively) and the kidneys (2.20 and 3.95% ID/g, respectively), followed by the lungs (0.31 and 0.73% ID/g), muscle (0.27 and 0.78% ID/g), heart (0.19 and 0.41% ID/g), and brain (0.11 and 0.19% ID/g). The LPS-treated mice exhibited ~30% increase in [18F]iNOS-9 accumulation in most of the organs as compared with the control mice. In the lungs (the LPS-targeted organ), LPS-treated mice showed iNOS increases of 30% at 5 min, 60% at 30 min, and 130% at 60 min. Co-administration of the selective iNOS inhibitor 1400W (5 mg/kg) with [18F]iNOS-9 blocked the tracer accumulation in the lungs and blood by >32% (P < 0.05) at 60 min after injection. The expression of iNOS was confirmed with Western blot analysis of lung homogenates from the LPS-treated mice. Dynamic [18F]iNOS-9 PET scans were performed for 60 min in one normal mouse and one LPS-treated mouse. The lungs in the LPS-treated mouse were clearly visualized at 60 min after injection but the lungs of the normal mouse were not.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

NIH Support

HL13851, CA86307

References

1.
Stuehr D.J. Mammalian nitric oxide synthases. Biochim Biophys Acta. 1999;1411(2-3):217–30. [PubMed: 10320659]
2.
Nathan C. Nitric oxide as a secretory product of mammalian cells. Faseb J. 1992;6(12):3051–64. [PubMed: 1381691]
3.
Hobbs A.J., Higgs A., Moncada S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu Rev Pharmacol Toxicol. 1999;39:191–220. [PubMed: 10331082]
4.
Lechner M., Lirk P., Rieder J. Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin Cancer Biol. 2005;15(4):277–89. [PubMed: 15914026]
5.
Zhou D., Lee H., Rothfuss J.M., Chen D.L., Ponde D.E., Welch M.J., Mach R.H. Design and synthesis of 2-amino-4-methylpyridine analogues as inhibitors for inducible nitric oxide synthase and in vivo evaluation of [18F]6-(2-fluoropropyl)-4-methyl-pyridin-2-amine as a potential PET tracer for inducible nitric oxide synthase. J Med Chem. 2009;52(8):2443–53. [PMC free article: PMC2782628] [PubMed: 19323559]

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