PET imaging of cyclooxygenase-2 (COX-2) in a pre-clinical colorectal cancer model

Abstract

BackgroundCyclooxygenase-2 (COX-2) is the inducible isoform of the cyclooxygenase enzyme family. COX-2 is involved in tumor development and progression, and frequent overexpression of COX-2 in a variety of human cancers has made COX-2 an important drug target for cancer treatment. Non-invasive imaging of COX-2 expression in cancer would be useful for assessing COX-2-mediated effects on chemoprevention and radiosensitization using COX-2 inhibitors as an emerging class of anti-cancer drugs, especially for colorectal cancer. Herein, we describe the radiopharmacological analysis of [18F]Pyricoxib, a novel radiolabeled COX-2 inhibitor, for specific PET imaging of COX-2 in colorectal cancer.MethodsUptake of [18F]Pyricoxib was assessed in human colorectal cancer cell lines HCA-7 (COX-2 positive) and HCT-116 (COX-2 negative). Standard COX-2 inhibitors were used to test for specificity of [18F]Pyricoxib for COX-2 binding in vitro and in vivo. PET imaging, biodistribution, and radiometabolite analyses were included into radiopharmacological evaluation of [18F]Pyricoxib.ResultsRadiotracer uptake in COX-2 positive HCA-7 cells was significantly higher than in COX-2 negative HCT-116 cells (P < 0.05). COX-2 inhibitors, celecoxib, rofecoxib, and SC58125, blocked uptake of [18F]Pyricoxib in HCA-7 cells in a concentration-dependent manner. The radiotracer was slowly metabolized in mice, with approximately 60 % of intact compound after 2 h post-injection. Selective COX-2-mediated tumor uptake of [18F]Pyricoxib in HCA-7 xenografts was confirmed in vivo. Celecoxib (100 mg/kg) selectively blocked tumor uptake by 16 % (PET image analysis; P < 0.05) and by 51 % (biodistribution studies; P < 0.01).ConclusionsThe novel PET radiotracer [18F]Pyricoxib displays a promising radiopharmacological profile to study COX-2 expression in cancer in vivo.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0192-9) contains supplementary material, which is available to authorized users.

Development of a 18F‐labeled Diaryl‐Substituted Dihydropyrrolo[3,2,1‐hi]indole as Potential Probe for Functional Imaging of Cyclooxygenase‐2 with PET

“…Interestingly, in majority of mice radiotracer accumulation in A2058 tumor was more pronounced in the peripheral zone of the tumor (tumor rim) compared to the tumor core (Figure B), a phenomenon already observed by Tietz et al …”

“…also observed 43 % of radioactivity in blood cells at 60 min p.i. using the methylsulfonyl substituted [ 18 F]pyricoxib . Further metabolite analysis in urine and feces revealed that [ 18 F] DHPI was excreted in form of at least three more hydrophilic radioactive metabolites (Figure B).…”

Evaluation of Two Potent and Selective PET Radioligands to Image COX-1 and COX-2 in Rhesus Monkeys

“…Shukuri et al studied 11 C-ketoprofen methyl ester, which has 62-fold higher selectivity for COX-1 than for COX-2, in rodents and humans (8)(9)(10); however, this agent is confounded by quantitation issues for the radiolabeled prodrugs, making it difficult to distinguish whether radioactivity is retained in brain because of high-affinity binding to COX-1 or merely by trapping of the negatively charged acid. With regard to PET radioligands for COX-2, no results have been published from human or nonhuman primates, although a few candidate radioligands have been studied in rodent inflammation models (11)(12)(13).…”

“…Toward this end, our laboratory recently developed 2 PET radioligands, 11 C-PS13 ( 11 C-1,5-bis-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-1,2,4-triazole) and 11 C-MC1 ( 11 C-6-methoxy-2-(4-(methylsulfonyl)phenyl)-N-(thiophen-2-ylmethyl)pyrimidin-4-amine), which are potent and selective for COX-1 and COX-2, respectively ( Fig. 1) (14)(15)(16).…”

Visualisierung molekularer Zielstrukturen bei Entzündungen und Infektionen

“…Weiterhin wurden 18 F-und 11 C-markierte Substanzen entwickelt, deren In-vivo-Stabilität und Lipophilie entweder mangelhaft war oder deren Bindung keine hohe Affinität und Selektivität für die Zielstruktur zeigte [77]. Hier wurde aktuell ein neuer fluorierter Tracer entwickelt ( 18 F-Pyricoxib), der im Tiermodell die geforderten Eigenschaften erfüllt [65,142].…”