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Basic Science Investigations |
1 Institute of Radioisotopes–Radiodiagnostic Products, National Center for Scientific Research Demokritos, Athens, Greece
2 Department of Nuclear Medicine, Philipps University Marburg, Marburg, Germany
3 Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland
The aim of this study was to evaluate 3 new 99mTc-labeled minigastrin analogs modified with open chain tetraamines at the N-terminus for their suitability in the CCK-2/gastrin-R–targeted imaging of tumors (CCK-2/gastrin-R = cholecystokinin subtype 2/gastrin receptor). Methods: The [(D)Glu1]minigastrin sequence was assembled on the solid support and the respective tetraamine precursors coupled at the N-terminus. Purified peptide conjugates were labeled with 99mTc under alkaline conditions. Saturation binding experiments were performed for (radio)metallated peptides [99mTc/99gTc]Demogastrin 1–3 in rat acinar pancreatic AR4-2J cell membranes. Internalization was studied in AR4-2J cells at 37°C. Radiopeptide stability was tested in murine plasma, urine, and kidney homogenates. Tissue distribution of the peptides was compared in healthy mice and athymic mice bearing AR4-2J tumors. Results: Peptide conjugates were obtained in 10%–30% overall yields by solid-phase techniques. Radiolabeling afforded >98% pure [99mTc]Demogastrin 1–3 species in specific activities of 
37 GBq/µmol. Radiopeptides retained a high affinity for the CCK-2/gastrin-R in vitro (50% inhibitory concentration values of 1 nmol/L) and internalized rapidly in CCK-2/gastrin-R–positive cells. After injection in mice they displayed rapid, high, and specific localization in the CCK-2/gastrin-R–expressing tissues (stomach and AR4-2J tumor) and were excreted from the body via the kidneys in the form of hydrophilic metabolites. Conclusion: The promising characteristics of [99mTc]Demogastrin 1–3 both in vitro and in animal models illustrate their suitability for CCK-2/gastrin-R–targeted tumor imaging. These qualities could be confirmed for [99mTc]Demogastrin 2, which provided excellent delineation of tumor deposits in a first patient with metastatic medullary thyroid cancer.
Key Words: tetraamine-peptides • cholecystokinin-2/gastrin-receptor • tumor targeting • 99mTc-labeled minigastrin
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