Euromedim 2006 :1st European Conference on Molecular Imaging Technology

Preclinical evaluation of new radioligands of cholecystokinin/gastrin receptors in endocrine tumours xenograft nude mice.

12 May 2006, 10:00

15m

Palais du Pharo, Marseille

oral S9_S10 Molecular Imaging Molecular Imaging

Speaker

Dr SEVERINE BRILLOUET (INSTITUT CLAUDIUS REGAUD)

Description

Aim: Whereas somatostatin receptor scintigraphy has been proven a valuable tool for staging gastrointestinal endocrine tumors, its sensitivity and accuracy in other neoplasm, 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 all these tumours and metastasis or that the expression of these receptors can change during the evolution of the pathology. The CCK-2 (cholecystokinin)/gastrin receptors (RCCK2) are overexpressed in up to 90% of MTC and 60% in SCLC but not in corresponding healthy tissues. Thus, they represent an ideal target for the diagnosis and internal radiotherapy of these tumours. The objective of our study was to compare previously published CCK radioligands (111In- DTPA-CCK8) to newly synthesized ligands of the RCCK2 containing new generations of metal chelating in order to increase the efficacy of the RCCK2 targeting and to limit nephrotoxicity. Materials and Methods: Derivatives of CCK8, CCK4 and gastrin peptides have been developed and were covalently coupled to the new synthetized chelating agents to be further labelled with 111Indium. The stability and affinity of the radiolabelled peptide were studied in vitro and in vivo. Nude mice, bearing tumors from the human SCLC cell line NCI-H69 and the human MTC cell line TT, were intravenously injected with 10 MBq of radiolabelled peptide. In vivo scintigraphy of these various peptides were performed 24 h post injection : a dynamic acquisition of planar images was performed using a gamma camera (Millennium VG-GEHC) equipped with low energy high resolution collimators. Images analysis was done on a Xeleris workstation (GEHC-Waukesha). Thereafter biodistribution studies (%ID/g tissue ) were done with a gamma counter (Wallac Wizard). Results: We have elaborated and optimised the conditions of radiolabelling leading to a radiochemical purity > 85%. In vitro studies confirmed that the CCK compounds tested displayed a high affinity for the RCCK2 (nanomolar range). Scintigraphic studies of xenograft mice showed significant tumour uptake with a high target to non target ratio. Ex vivo studies confirmed the efficiency of RCCK2 targeting with these original radiolabelled CCK analogs. A biodistribution study showed physiological distribution (stomach, pancreas), renal excretion (gallbladder, kidneys) and tumor uptake at 24 h post injection. Conclusion: According to these studies, these new radiolabelled compounds seem to have promised stability and high receptor affinity thus these “optimised” CCK ligands coupled to specific chelators might be potential new candidates for molecular imaging and internal radiotherapy of tumours overexpressing the RCCK2 receptors.