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CCK-2/gastrin receptor-targeted tumor imaging with (99m)Tc-labeled minigastrin analogs
Berthold A Nock1, Theodosia Maina, Martin Béhé
1Institute of Radioisotopes-Radiodiagnostic Products, National Center for Scientific Research Demokritos, Athens, Greece. nockb@rrp.demokritos.gr
Unlabelled:
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.
Conclusion:
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.
Insights
New technetium-99m labeled minigastrin analogs show promise for cholecystokinin subtype 2/gastrin receptor-targeted tumor imaging. One analog, [(99m)Tc]Demogastrin 2, demonstrated excellent tumor delineation in a patient with metastatic medullary thyroid cancer.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Oncology imaging
Background:
- Cholecystokinin subtype 2/gastrin receptor (CCK-2/gastrin-R) is a target for tumor imaging.
- Development of targeted radiopharmaceuticals is crucial for accurate cancer detection.
- Minigastrin analogs are being explored for their potential in CCK-2/gastrin-R imaging.
Purpose of the Study:
- To evaluate three novel (99m)Tc-labeled minigastrin analogs for CCK-2/gastrin-R-targeted tumor imaging.
- To assess the in vitro and in vivo characteristics of these radiolabeled peptides.
Main Methods:
- Solid-phase synthesis of minigastrin analogs with N-terminal tetraamine modifications.
- Radiolabeling with (99m)Tc under alkaline conditions.
- In vitro binding and internalization studies in AR4-2J cells, stability tests in murine plasma, and biodistribution studies in mice.
Main Results:
- High purity radiolabeling (>98%) and specific activities achieved for [(99m)Tc]Demogastrin 1-3.
- Radiopeptides exhibited high affinity for CCK-2/gastrin-R, rapid internalization, and specific tumor localization in animal models.
- Efficient renal excretion of hydrophilic metabolites was observed.
Conclusions:
- [(99m)Tc]Demogastrin 1-3 analogs possess promising characteristics for CCK-2/gastrin-R-targeted tumor imaging.
- [(99m)Tc]Demogastrin 2 showed excellent tumor delineation in a patient with metastatic medullary thyroid cancer, confirming its clinical potential.
