CCK-2/gastrin receptor-targeted tumor imaging with (99m)Tc-labeled minigastrin analogs.
The aim of this study was to evaluate 3 new (99m)Tc-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)Glu(1)]minigastrin sequence was assembled on the solid support and the respective tetraamine precursors coupled at the N-terminus. Purified peptide conjugates were labeled with (99m)Tc under alkaline conditions. Saturation binding experiments were performed for (radio)metallated peptides [(99m)Tc/(99g)Tc]Demogastrin 1-3 in rat acinar pancreatic AR4-2J cell membranes. Internalization was studied in AR4-2J cells at 37 degrees 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 [(99m)Tc]Demogastrin 1-3 species in specific activities of approximately 37 GBq/mumol. Radiopeptides retained a high affinity for the CCK-2/gastrin-R in vitro (50% inhibitory concentration values of approximately 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.


CONCLUSIONS
The promising characteristics of [(99m)Tc]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 [(99m)Tc]Demogastrin 2, which provided excellent delineation of tumor deposits in a first patient with metastatic medullary thyroid cancer.
Nock
Berthold A
BA
Institute of Radioisotopes-Radiodiagnostic Products, National Center for Scientific Research Demokritos, Athens, Greece. nockb@rrp.demokritos.gr
Maina
Theodosia
T
Béhé
Martin
M
Nikolopoulou
Anastasia
A
Gotthardt
Martin
M
Schmitt
Jörg S
JS
Behr
Thomas M
TM
Mäcke
Helmut R
HR
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D005755:Gastrins / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008875:Middle Aged; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D043887:Receptor, Cholecystokinin B / Q000378:metabolism*; D014018:Tissue Distribution
D014408:Biomarkers, Tumor; D005755:Gastrins; D019275:Radiopharmaceuticals; D043887:Receptor, Cholecystokinin B; C008530:minigastrin