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Développement d'analogues urotensinergiques radiomarqués pour l'imagerie de tumeurs solides

Abstract : Overexpression of G protein-coupled receptors (GPCRs) in tumor is widely used to develop GPCR-targeting radioligands for solid tumor imaging. For example, somatostatin analogue labeled with 111Indium (111In-OctreoScan) is used for the diagnosis of neuroendocrine tumors. The vasoactive neuropeptide urotensin II (UII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumors from lung, gut, prostate or breast, suggesting that UT is a valuable target to design radiolabeled UII analogues for cancer diagnosis. Two urotensinergic analogues (DOTA-UII and DOTA-urantide) both containing the DOTA chelating group capable of complexing radioactive metal isotopes have been synthetized and radiolabeled with 111Indium. Incubation of 111In-DOTA-UII in human plasma revealed that only 30% of the radioligand was degraded after a 3h incubation period. Administration of graded concentrations of both DOTA-UII and DOTA-urantide in the vicinity of HEK293 cells expressing UT induced a dose-dependent increase in cytosolic calcium concentration, with similar potency and efficacy to that obtained with UII and urantide. These results demonstrated that conjugation of DOTA in urotensinergic analogues did not affect UT activation. DOTA-UII was also able to promote UT internalization in HEK293 cells expressing UT, while DOTA-urantide was ineffective. Intravenous injection of 111In-DOTA-UII in C57BL/6 mice revealed a slight signal mostly restricted in kidney, and similar results were obtained with knock-out mice or constitutively expressing human UT mice. Finally, 111In-DOTA-UII was injected into nude mice bearing heterotopic xenografts of human A549 cells (lung adenocarcinoma) or DLD-1 cells (colorectal adenocarcinoma) both expressing functional UT. In both cases, SPECT-CT imaging showed the absence of tumor uptake and significant renal and bladder uptakes, suggesting fast tracer clearance from the organism. However, further investigations will be necessary to decrease renal clearance and to improve tumor imaging.
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Submitted on : Friday, July 13, 2018 - 11:21:35 AM
Last modification on : Thursday, November 28, 2019 - 3:23:58 AM
Long-term archiving on: : Monday, October 15, 2018 - 11:17:20 PM


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  • HAL Id : tel-01838279, version 1


Benjamin Poret. Développement d'analogues urotensinergiques radiomarqués pour l'imagerie de tumeurs solides. Cancer. Normandie Université, 2018. Français. ⟨NNT : 2018NORMR028⟩. ⟨tel-01838279⟩