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Radioiodinated indomethacin amide for molecular imaging of cyclooxygenase-2 expressing tumors
Agnieszka Morgenroth1, Andreas T J Vogg1, Bernd Neumaier2,3,4
1Department for Nuclear Medicine, RWTH Aachen University Hospital, 52074, Aachen, Germany.
Abstract:
Cyclooxygenase-2 (COX-2) is an important biomarker in several tumors. Available imaging probes display relatively low tumor to background ratios (smaller than 2:1). We evaluated newly developed indomethacin (Ind) derivatives for in vivo molecular imaging of COX-2 expressing carcinoma. Radioiodinated Ind derivatives Ind-NH-(CH2)4-NH-3-[I-125]I-Bz ([I-125]5), Ind-NH-(CH2)4-NH-5-[I-124/125]I-Nic ([I-124/125]6) and Ind-NH-(CH2)4-NH-5-[I-125]I-Iphth ([I-125]7) were prepared from the respective SnBu3-precursors (45-80% radiochemical yield; > 95% radiochemical purity). The cellular uptake of [I-125]5 and [I-125]6 correlated with COX-2 expression determined by SDS page/Western blot analysis. [I-125]5 was predominantly localized in the cell membrane while [I-125]6 was internalized and displayed a diffuse and favorable cytoplasmic distribution. In contrast, [I-125]7 showed only low uptake in COX-2 positive cells. Co-incubation with the COX-2 inhibitor Celecoxib led to an almost complete suppression of cellular uptake of [I-125]5 and [I-125]6. In vivo molecular imaging using positron emission tomography (PET) in SCID mice xenografted with COX-2+ (HT29) and COX-2- (HCT116) human colorectal carcinoma cells was performed for [I-124]6. HT29 xenografts displayed a significantly higher uptake than HCT-116 xenografts (5.6 ± 1.5 vs. 0.5 ± 0.1 kBq/g, P < 0.05) with an extraordinary high tumor to muscle ratio (50.3 ± 1.5). Immunohistological staining correlated with the imaging data. In conclusion, the novel radioiodinated indomethacin derivative ([I-124/125]6) could become a valuable tool for development of molecular imaging probes for visualization of COX-2 expressing tumors.
Insights
New indomethacin derivatives were developed for imaging cyclooxygenase-2 (COX-2) tumors. The radioiodinated derivative [I-124/125]6 showed high tumor uptake and excellent tumor-to-muscle ratios in preclinical models, indicating its potential for COX-2 visualization.
Area of Science:
- Molecular imaging and diagnostics
- Oncology and cancer biomarkers
- Radiopharmaceutical chemistry
Background:
- Cyclooxygenase-2 (COX-2) is a significant biomarker in various human cancers.
- Existing imaging probes for COX-2 exhibit suboptimal tumor-to-background ratios, limiting their clinical utility.
- There is a need for novel, high-performance imaging agents for COX-2-expressing tumors.
Purpose of the Study:
- To evaluate novel indomethacin derivatives as potential in vivo molecular imaging agents for COX-2.
- To assess the cellular uptake, biodistribution, and tumor targeting capabilities of these new compounds.
- To determine the feasibility of using these agents for positron emission tomography (PET) imaging of COX-2-positive carcinomas.
Main Methods:
- Synthesis and radioiodination of novel indomethacin derivatives, including [I-125]5, [I-124/125]6, and [I-125]7.
- In vitro evaluation of cellular uptake in COX-2 expressing cells and competition assays with Celecoxib.
- In vivo preclinical imaging studies using PET in SCID mice xenografted with human colorectal carcinoma cells (HT29 COX-2+ and HCT116 COX-2-).
Main Results:
- Radioiodinated indomethacin derivatives ([I-125]5 and [I-124/125]6) demonstrated COX-2-dependent cellular uptake.
- The derivative [I-124/125]6 exhibited favorable cytoplasmic localization and was successfully used for PET imaging.
- In vivo PET imaging revealed significantly higher uptake of [I-124/125]6 in COX-2 positive HT29 xenografts compared to COX-2 negative HCT116 xenografts, achieving an exceptional tumor-to-muscle ratio of 50.3 ± 1.5.
Conclusions:
- The novel radioiodinated indomethacin derivative [I-124/125]6 shows promising potential as a molecular imaging probe.
- This agent enables effective visualization of COX-2 expressing tumors with high contrast in preclinical models.
- [I-124/125]6 could be a valuable tool for the future development of diagnostic imaging agents for COX-2-positive cancers.