Development of PET Radioligands Targeting COX-2 for Colorectal Cancer Staging, a Review of in vitro and Preclinical Imaging Studies

Abstract

Colorectal cancer (CRC) is the second most common cause of cancer death, making early diagnosis a major public health challenge. The role of inflammation in tumorigenesis has been extensively explored, and among the identified markers of inflammation, cyclooxygenase-2 (COX-2) expression seems to be linked to lesions with a poor prognosis. Until now, COX-2 expression could only be accessed by invasive methods, mainly by biopsy. Imaging techniques such as functional Positron Emission Tomography (PET) could give access to in vivo COX-2 expression. This could make the staging of the disease more accurate and would be of particular interest in the exploration of the first metastatic stages. In this paper, we review recent progress in the development of COX-2 specific PET tracers by comparing the radioligands' characteristics and highlighting the obstacles that remain to be overcome in order to achieve the clinical development of such a radiotracer, and its evaluation in the management of CRC.

New insights into the characteristics of DRAK2 and its role in apoptosis: From molecular mechanisms to clinically applied potential

“…COX-2 expression in normal cells is rare and almost negligible ( Gurram et al, 2018 ), and its frequent appearance in cancer is considered a marker for cancer detection ( Hashemi Goradel et al, 2019 ). Some studies have shown that COX-2 expression is increased in most CRC patients, suggesting that COX-2 is closely related to CRC ( Wang and Dubois, 2010 ; Su et al, 2016 ; Dagallier et al, 2021 ). Interestingly, when the COX-2 selective inhibitor rofecoxib was administered to CRC patients, the DRAK2 level in tumor cells increased 2.5-fold.…”

Investigation of Radiotracer Metabolic Stability In Vitro with CYP-Overexpressing Hepatoma Cell Lines

“…For cyclooxygenase (COX), two different isoforms are known; COX-1 is constituently expressed, while COX-2 is absent in healthy tissues with the exception of heart, kidney, and brain, but is inducible under inflammatory conditions. Radiotracers that target COX-2 are, therefore, under investigation to image inflammatory processes and tumors in vivo [ 24 , 25 , 26 , 27 ]. On the basis of our interest in radiolabeled COX-2 inhibitors and our previous work covering the liver microsomal stability of fluorine-18-labeled celecoxib derivatives, compounds [ 18 F]1–3 [ 28 ], subsequently also referred to as 18 F-labeled coxibs, were chosen for this study.…”

Fluorine-18 Labelled Radioligands for PET Imaging of Cyclooxygenase-2

“…COX-2 plays a crucial role in tumorigenicity, angiogenesis, metastasis, and apoptosis-resistance in cancer, including colorectal, pancreatic, brain, and breast cancer. Moreover, COX-2 is frequently upregulated in cancer, making COX-2 a promising biomarker for cancer diagnosis and therapy, as demonstrated by the development of various fluorescent [49][50][51][52][53] and radioimaging probes over the last decades [54][55][56][57]. COX-2-targeting fluorescent probes mainly consist of a fluorescent group attached to known anti-inflammatory drugs.…”

“…There has also been significant progress in the development of COX-2-targeting radioligands for imaging inflammation, cancer, and neurological disorders [54][55][56][57]. Over the last decades, a variety of radionuclide-based imaging agents have been developed by the incorporation of radioisotopes such as 11 C, 18 F, 99m Tc, 123 I, and 125 I into NSAIDs and related compounds [55,56,[58][59][60][61][62][63][64][65][66][67][68][69][70][71]. Selected examples of PET radioligands for COX-2 imaging are presented in Figure 3 Molecules 2022, 27, x FOR PEER REVIEW 3 of 20…”

“…There has also been significant progress in the development of COX-2-targeting radioligands for imaging inflammation, cancer, and neurological disorders [54][55][56][57]. Over the last decades, a variety of radionuclide-based imaging agents have been developed by the incorporation of radioisotopes such as 11 C, 18 F, 99m Tc, 123 I, and 125 I into NSAIDs and related compounds [55,56,[58][59][60][61][62][63][64][65][66][67][68][69][70][71]. Selected examples of PET radioligands for COX-2 imaging are presented in Figure 3 A major focus involves 18 F-labeled radioligands, due to their favourable half-life (t1/2 = 109.8 min), ease of production, the availability of a variety of radiofluorination methods, and better imaging characteristics of the short-lived positron emitter 18 F. This review article primarily covers 18 F-labeled radioligands reported in the last decade for targeting COX-2.…”