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Cholecystokinin-2 Receptor Targeting with Novel C-terminally Stabilized HYNIC-Minigastrin Analogs Radiolabeled with Technetium-99m

The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, h...

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Detalles Bibliográficos
Autores principales: Klingler, Maximilian, Rangger, Christine, Summer, Dominik, Kaeopookum, Piriya, Decristoforo, Clemens, von Guggenberg, Elisabeth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469167/
https://www.ncbi.nlm.nih.gov/pubmed/30650563
http://dx.doi.org/10.3390/ph12010013
Descripción
Sumario:The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, high availability and low cost of technetium-99m ((99m)Tc)-labeled radiopharmaceuticals we have developed two hydrazinonicotinic acid (HYNIC) conjugated minigastrin analogs allowing labeling at high specific activity. The CCK2R targeting peptide conjugates show specific amino acid substitutions in the C-terminal receptor-specific sequence with the aim to increase stability and tumor targeting. The CCK2R affinity and the cell uptake of the new radioligands were analyzed using A431 human epidermoid carcinoma cells stably transfected with human CCK2R and mock transfected cells. Metabolic studies in BALB/c mice revealed a high resistance against enzymatic degradation for both radioligands. Biodistribution studies in tumor-xenografted athymic BALB/c nude mice at 1 h and 4 h p.i. showed that the two (99m)Tc-labeled compounds showed varying uptake in receptor expressing organs, stomach and pancreas (1.3–10.4% IA/g), as well as kidneys, the main route of excretion (7.8–19.9% IA/g). The tumor uptake in A431-CCK2R xenografts was 24.75 ± 4.38% IA/g for [(99m)Tc]Tc-HYNIC-MGS5 and 42.48 ± 6.99% IA/g for [(99m)Tc]Tc-HYNIC-MGS11 at 4 h p.i., whereas the tumor-to-kidney ratio was comparable (2.6–3.3). On demand availability and potential application for radioguided surgery of a (99m)Tc-labeled minigastrin analog support the further evaluation of these highly promising new compounds.