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Published on: May 8, 2017
Fluorinated COX-2 inhibitors as agents in PET imaging of inflammation and cancer
Md Jashim Uddin1, Brenda C Crews, Kebreab Ghebreselasie
1A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology, TN, USA.
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.
Insights
Novel fluorinated imaging agents targeting cyclooxygenase-2 (COX-2) show promise for cancer detection. These agents selectively bind to COX-2 in inflamed tissues and tumors, enabling effective molecular imaging for early diagnosis and treatment evaluation.
Area of Science:
- Biomedical imaging
- Molecular imaging
- Radiochemistry
Background:
- Cyclooxygenase-2 (COX-2) is crucial in inflammation and cancer progression.
- High COX-2 levels in inflammatory lesions and tumors make it an ideal molecular imaging target.
- Novel imaging agents are needed for selective COX-2 detection.
Purpose of the Study:
- To develop and evaluate novel fluorinated imaging agents for selective COX-2 inhibition and molecular imaging.
- To assess the in vitro and in vivo efficacy of a lead compound (compound 7) derived from celecoxib.
Main Methods:
- Synthesis of novel fluorinated COX-2 inhibitors based on indomethacin and celecoxib.
- In vitro kinetic analysis to determine inhibitory activity against COX-1 and COX-2.
- Radiochemical synthesis of (18)F-labeled compound 7 for positron emission tomography (PET) imaging.
- In vivo studies in rodent models of inflammation and cancer xenografts.
Main Results:
- Compound 7 demonstrated slow, tight-binding inhibition of COX-2 with minimal COX-1 activity.
- (18)F-labeled compound 7 was successfully synthesized and suitable for PET imaging.
- Selective uptake of (18)F-7 was observed in inflamed rat paws and COX-2-expressing human tumor xenografts.
- Uptake was COX-2 dependent, as shown by studies in COX-2-null mice and blockade experiments with celecoxib.
Conclusions:
- Compound 7 is a potent and selective COX-2 inhibitor with excellent properties for molecular imaging.
- The developed (18)F-labeled agent enables sensitive in vivo detection of COX-2 expression in inflammation and tumors.
- This probe holds potential for early cancer detection and evaluating COX-2 status in premalignant and malignant lesions.
