Preclinical evaluation of new radioligand of cholecystokinin/gastrin receptors in endocrine tumors xenograft nude mice

摘要

The cholecystokinin(CCK)/gastrin 2 receptors (R-CCK2) are overexpressed in 90% of medullary thyroid cancers (MTC) and in 60% of small cell lung cancers but not or poorly in corresponding healthy tissues. They represent a relevant target for the diagnosis and internal targeted radiotherapy of these tumors. Although previous studies have demonstrated the feasibility of radiolabeled CCK/gastrin to target CCK-2 receptor-expressing tissues in animals and patients, some problems remained unsolved to identify an optimum candidate for in vivo targeting of R-CCK2-expressing tumors. By a rational approach and "in silico" drug design, we synthesized a new CCK-derivative with high affinity for the R-CCK2. The aim of this study was to achieve the radiolabeling of a new radioligand, to assess its efficacy using a published CCK radioligand (~(111)In-DTPA-CCK8) as a control for the R-CCK2 targeting.rnThis new CCK-derivative was radiolabeled with ~(111)In. Nude mice, bearing the human MTC TT tumors and NIH-3T3 cell line expressing a tumorigenic mutant of the R-CCK2, were injected with this radiolabeled peptide. In vivo planar scintigraphies were acquired. Thereafter, biodistribution studies (%ID/g tissue) were done.rnThe conditions of radiolabelling were optimized to obtain a radiochemical purity > 90%. Scintigraphic images of xenograft mice showed significant tumor uptake with a target to nontarget ratio higher than two. These results were confirmed by the biodistribution studies which showed as expected a significant activity in the spleen, the liver and the kidneys.rnTherefore, this new radiolabeled compound is a promised new candidate for molecular imaging and internal radiotherapy for R-CCK2 tumor targeting.