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Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer.

ABSTRACT: COX-2 is a major contributor to the inflammatory response and cancer progression so it is an important target for prevention and therapy. COX-2 is absent or expressed at low levels in most epithelial cells but is found at high levels in inflammatory lesions, and many premalignant and malignant tumors. Thus, it is an attractive target for molecular imaging. We report a series of novel fluorinated imaging agents, derived from indomethacin or celecoxib that selectively inhibit COX-2. The most promising lead, compound 7, was a fluorinated derivative of celecoxib. Kinetic analysis revealed that this fluorinated compound is a slow, tight-binding inhibitor of COX-2 and exhibits minimal inhibitory activity against COX-1. Efficient incorporation of (18)F into compound 7 by radiochemical synthesis and intravenous injection provided sufficient signal for in vivo positron emission tomography (PET) imaging. Selective uptake of (18)F-7 was observed in inflamed rat paws compared with the noninflamed contralateral paws and uptake was blocked by pretreatment with the COX-2 inhibitor, celecoxib. Uptake of (18)F-7 was not observed when inflammation was induced in COX-2-null mice. In nude mice bearing both a COX-2-expressing human tumor xenograft (1483) and a COX-2-negative xenograft (HCT116), (18)F-7 selectively accumulated in the COX-2-expressing tumor. Accumulation was blocked by pretreatment of the animals with celecoxib. The in vitro and in vivo properties of compound 7 suggest it will be a useful probe for early detection of cancer and for evaluation of the COX-2 status of premalignant and malignant tumors.

SUBMITTER: Uddin MJ

PROVIDER: S-EPMC3214660 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer.

Uddin Md Jashim MJ Crews Brenda C BC Ghebreselasie Kebreab K Huda Imran I Kingsley Philip J PJ Ansari Mohammad Sib MS Tantawy Mohammed N MN Reese Jeffery J Marnett Lawrence J LJ

Cancer prevention research (Philadelphia, Pa.) 20110907 10

COX-2 is a major contributor to the inflammatory response and cancer progression so it is an important target for prevention and therapy. COX-2 is absent or expressed at low levels in most epithelial cells but is found at high levels in inflammatory lesions, and many premalignant and malignant tumors. Thus, it is an attractive target for molecular imaging. We report a series of novel fluorinated imaging agents, derived from indomethacin or celecoxib that selectively inhibit COX-2. The most promi ...[more]

PMID: 21900596

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Project description:Imaging of cholesterol use is possible with the 131I scintiscanning/SPECT agent NP-59. This agent provided a noninvasive measure of adrenal function and steroid synthesis. However, iodine isotopes resulted in poor resolution, manufacturing challenges, and high radiation dosimetry to patients that have limited their use and clinical impact. A 18F analog would address these shortcomings while retaining the ability to image cholesterol use. The goal of this study was to prepare and evaluate a 18F analog of NP-59 to serve as a PET imaging agent for functional imaging of the adrenal glands based on cholesterol use. Previous attempts to prepare such an analog of NP-59 have proven elusive. Preclinical and clinical evaluation could be performed once the new fluorine analog of NP-59 production was established. Methods: The recent development of a new reagent for fluorination along with an improved route to the NP-59 precursor allowed for the preparation of a fluorine analog of NP-59, FNP-59. The radiochemistry for the 18F-radiolabeled 18F-FNP-59 is described, and rodent radiation dosimetry studies and in vivo imaging in New Zealand rabbits was performed. After in vivo toxicity studies, an investigational new drug approval was obtained, and the first-in-humans images with dosimetry using the agent were acquired. Results: In vivo toxicity studies demonstrated that FNP-59 is safe for use at the intended dose. Biodistribution studies with 18F-FNP-59 demonstrated a pharmacokinetic profile similar to that of NP-59 but with decreased radiation exposure. In vivo animal images demonstrated expected uptake in tissues that use cholesterol: gallbladder, liver, and adrenal glands. In this first-in-humans study, subjects had no adverse events and images demonstrated accumulation in target tissues (liver and adrenal glands). Manipulation of uptake was also demonstrated with patients who received cosyntropin, resulting in improved uptake. Conclusion: 18F-FNP-59 provided higher resolution images, with lower radiation dose to the subjects. It has the potential to provide a noninvasive test for patients with adrenocortical diseases.

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Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer.

Publications

Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer.

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