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Whereas somatostatin receptor scintigraphy has been proven a valuable tool for staging gastrointestinal endocrine tumors, its sensitivity and accuracy in other cancers, such as metastatic medullary thyroid cancer (MTC) or small cell lung cancer (SCLC), is limited by the fact that the somatostatin receptors are not expressed in these tumors and metastasis or that their expression change during the evolution of the pathology. The cholecystokinin/gastrin receptor (CCK2R) is overexpressed in up to 90% of MTC and 60% of SCLC but not in the corresponding healthy tissues. Thus, the CCK2R represents a potential target for the diagnosis and internal radiotherapy of these tumors. Although previously studies had demonstrated the feasibility of radiolabeled CCK/gastrin ligands to target MTC in animals and patients, adverse effects using these peptides were reported indicating that tumor uptake, biodistribution and stability of the radioligand must be improved for clinical application.

Aim: The aim of this study was to synthesize new radioligands of the CCK2R with optimized properties to target the CCK2R in different tumor models. To this end, we have used a tri-dimensional molecular model of the CCK2R occupied by CCK that we have previously built to design “in silico” modified CCK derivatives covalently coupled to a chelating agent.

Materials and Methods: Two CCK derivatives (A and B) have been synthesized, covalently coupled to the chelating agent DTPA and labelled with 111Indium. The stability and affinity of these CCK derivatives were studied in vitro. Nude mice, bearing NIH-3T3 tumors expressing a constitutively active mutant of the CCK2R and MTC (TT) tumors, were intravenously injected with 10 MBq of radiolabelled CCK derivatives. In vivo scintigraphy was performed 24 h post injection and compared with the control 111In-DTPA-CCK8 used in the published studies. A dynamic acquisition of planar images was performed using a gamma camera equipped with medium energy collimators. Images analysis was done on a Xeleris workstation (GEHC-Waukesha). Thereafter biodistribution studies (% ID/g tissue ) were done with a gamma counter.

Results: The conditions of radiolabeling were achieved to lead to a radiochemical purity > 90%. In vitro studies confirmed that the two CCK compounds displayed nanomolar affinities for the CCK2R and greater stabilities. Scintigraphic and biodistribution studies of xenografted mice showed a 3-fold higher tumor uptake for the CCK derivative B compared to the control 111In-DTPA-CCK8 with a target to non target ratio higher than 2. In addition, the biodistribution studies of the CCK derivative B showed a physiological distribution as well as renal and gallbladder excretion.

Conclusion: This new radiolabeled CCK derivative appears as a promising candidate for molecular imaging and internal radiotherapy in two tumor models expressing the CCK2R.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA