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Minigastrin analogs for enhanced cholecystokinin-2 receptor targeting and their theranostic use

Dr Elisabeth von Guggenberg, Medical University of Innsbruck; Dr Maximilian Klingler, Medical University of Innsbruck

Ascenion GmbH


An attractive target for different tumors, especially neuroendocrine tumors like medullary thyroid carcinoma (MTC) and small cell lung cancers (SCLC) has been identified in the cholecystokinin-2 receptor (CCK2R). CCK2R is overexpressed also in different other neoplasms, and therefore, offers a highly personalized diagnostic and therapeutic approach for different cancers when safe and effective systemic therapies are missing. However, targeting CCK2R with natural ligands minigastrin and cholecystokinin did not result in a successful therapeutic application so far. Many attempts have been made to find CCK2R targeting ligands suitable for single photon emission tomography (SPECT), positron emission tomography (PET), and therapeutic applications using radiolabeled peptides. The first radiolabeled peptides developed were based on the endogenous ligands minigastrin and cholecystokinin. However, short physiological half-life, low enzymatic stability, low bioavailability, and high uptake in kidneys, the latter leading to nephrotoxic side effects in therapeutic applications, are shortfalls in view of high contrast molecular imaging and effective therapeutic success.


To address these problems and to provide an effective therapeutic as well as diagnostic approach for CCK2R targeting, different modifications of the peptide sequence of minigastrin analogs have been investigated. These especially included site-specific chemical modifications at the C-terminal receptor-binding part of the peptide. Substitution of Met against unnatural N-methylated (N-Me) norleucin (Nle) and substitution of Phe against 1-naphthylalanine (1-Nal) or (N-Me)Phe (marked in Figure aside) lead to a high stability of the metal complex in 111In-labelled and 177Lu-labelled DOTA-peptides against enzymatic degradation in vitro and in vivo. Due to this improved bioavailability, the peptide analogs showed retained and high receptor affinity and higher tumor cell uptake with reduced uptake in stomach and kidney in a xenograft mouse model. In small animal NanoSpect/CT imaging studies, a favorable distribution with reduced kidney uptake was found leading to high-contrast imaging.

Commercial Opportunity

It could be demonstrated that minigastrin analogs can be stabilized against enzymatic degradation in vivo without losing CCK2R affinity. This not only leads to minigastrin analogs with improved bioavailability, but more importantly significantly increases tumor uptake. Thus, the minigastrin analogs seem most suitable for CCK2R targeting and theranostic use with alternative radionuclides.

Development Status

A first clinical application for PET imaging is planned with a 68Ga-labelled minigastrin analog. For this purpose, a kit formulation has been developed allowing the standardized preparation of the radiopharmaceutical in the clinical setting. For further clinical translation, GMP material needs to be provided and an extended single dose toxicity study in rodents needs to be performed.

Patent Situation

A PCT patent application has been filed in June 2018 (priority June 2017).

Further Reading

Klingler et al. (2018), Theranostics 8:2896-2908

Rangger et al. (2017), Mol. Pharm. 14:3045-3058

Klingler M et al. (2019), Pharmaceuticals 12:13

Klingler M et al. (2018), J. Nucl. Med. [Epub ahead of print]


Minigastrin analogs for enhanced cholecystokinin-2 receptor targeting and their theranostic use