In Vitro and In Vivo Characterization of Indium-111 and Technetium-99m Labeled CCK-8 Derivatives for CCK-B Receptor Imaging

Cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with In-111 or Tc-99m for CCK-B receptor imaging. Derivatives of CCK8 were obtained by addition at the N-terminus in solid phase of a DTPA derivative (DTPAGlu) linked through a glycine spacer (DTPAGlu-G-CCK8) or cysteine, glycine and a diphenylphosphinopropionyl moiety (PhosGC-CCK8) for labeling with In-111 and 99mTc, respectively. CCK-BR overexpressing A431 cancer cell lines were utilized to characterize in vitro Properties of the two compounds as well as for generating xenografts in nude mice for in vivo characterization. Both In-111-DTPAGlu-G-CCK8 and (99m)TcPhosGC-CCK8 showed similar binding affinities for CCK-BR with dissociation constants of 20-40 nM, were internalized after interaction with the receptor and displayed prolonged cellular retention times. Specific in vivo interaction with the receptor of both CCK8 analogs was observed in our animal model In-111-DTPAGlu-G-CCK8 showed better target to non-target ratios, although it appeared to be rapidly metabolized after injection and activity cleared through the kidneys. Tc-99m-PhosGC-CCK8 was more stable in vivo but showed marked hepatobiliary clearance with resulting high background activity in the bowel. The rapid clearance and lower background obtained with 111In-DTPAGlu-G-CCK8 make this a better candidate for further development.