Radioiodinated indomethacin amide for molecular imaging of cyclooxygenase-2 expressing tumors.

Agnieszka Morgenroth,Boris D Zlatopolskiy,Bernd Neumaier,Andreas T.J Vogg,Felix M Mottaghy

doi:10.18632/oncotarget.15437

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.

Highlights

Cyclooxygenase-2 (COX-2) represents an attractive target for molecular imaging due to its unique graded expression patterns in normal, inflamed and malignant tissues [1, 2]
We evaluated newly developed indomethacin (Ind) derivatives for in vivo molecular imaging of COX-2 expressing carcinoma
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

Summary

Introduction

Cyclooxygenase-2 (COX-2) represents an attractive target for molecular imaging due to its unique graded expression patterns in normal, inflamed and malignant tissues [1, 2]. In contrast to the COX1 isoform, which is constitutively expressed in most physiological tissues, COX-2 transcription is induced by a wide spectrum of growth factors and cytokines in specific pathophysiological conditions. Both isoforms are localized in the endoplasmatic reticulum (ER) and in the nuclear envelope and convert arachidonic acid to prostaglandins and thromboxane, which mediate different responses within the immediate environment [3]. COX-2 expression levels have been shown to be a prognostic marker for transformation from ductal carcinoma in situ to invasive growth and generation of metastases in breast cancer [5]. The correlation between cancer progression and increased COX-2 expression supports the concept of molecular imaging of COX-2 expression for detection and staging of cancer

Objectives

Methods

Results