Entwicklung und präklinische Evaluation von Radiopeptiden als Cholezystokinin-Rezeptor Liganden zur Tumordiagnostik und -therapie

INTRODUCTION: Various tumor types, e.g., small-cell lung cancer and medullary thyroid cancer, express cholecystokinin (CCK) surface receptors. The radiolabeled peptide minigastrin, consisting of 13 amino acids, has performed well in a preclinical setting for the detection of CCK2/gastrin receptor positive tissues in vivo. This thesis evaluates the performance of further selected, radiolabeled CCK- and gastrin-like peptides for the detection of CCK receptor positive tissues by stability and biodistribution studies. MATERIALS AND METHODS: Eleven peptides were linked with diethylene triamine pentaacetate (DTPA), purified, and labeled with 111-Indium. For stability studies, radiolabeled minigastrin and [D-Glu]1-minigastrin were exposed to human plasma proteins and excessive DTPA in vitro and 111-Indium transchelation was assessed by high performance liquid chromatography. In addition, a whole-body scintigraphy of a healthy human volunteer was performed after intravenous injection of 185 MBq of each of the two radiopeptides. For biodistribution studies, nude mice were administered 0.55 MBq of radiolabeled peptide intravenously and radioactivity of the animal, of blood samples, and of 10 dissected organs were quantified at 10 min, 1h, 4h, and 24 h and expressed as percentages of the initial doses per gram. N=2 animals were used for each of the 11 radiopeptides and for each observation period. RESULTS: [D-Glu]1-minigastrin showed enhanced stability in vitro and in vivo. Sulfated CCK8 and Cionin demonstrated significantly higher affinity for CCK1 and CCK2-/ gastrin receptors compared to their non-sulfated counterparts in vivo. All CCK-like and some gastrin-like radiolabeled peptides demonstrated a significantly reduced renal accumulation compared with minigastrin. CONCLUSION: Simple alterations by substitution and sulfatation of amino acids have a distinct impact on a radiolabelled peptide’s performance in vitro and in vivo with respect to stability, CCK receptor affinity and specificity, and renal accumulation.