Radiopharmaceutical Formulation and Preclinical Testing of 68Ga-Labeled DOTA-MGS5 for the Regulatory Approval of a First Exploratory Clinical Trial

The new minigastrin analog DOTA-MGS5 is a promising new candidate for targeting cholecystokinin-2 receptor (CCK2R)-expressing tumors. To enable the clinical translation of PET/CT imaging using Ga-68-labeled DOTA-MGS5, different quality and safety aspects need to be considered to comply with the regulatory framework for clinical trial application. The preparation of the radiopharmaceutical was established using a cassette-based automated synthesis unit. Product specifications, including analytical procedures and acceptance criteria, were adopted from Ph. Eur. monographs for other Ga-68-labeled radiopharmaceuticals. Non-clinical studies included receptor affinity and cell uptake studies using two different CCK2R-expressing cell lines, as well as pharmacokinetic biodistribution studies in BALB/c mice for dosimetry calculations and toxicological studies in Wistar rats. The produced masterbatches fulfilled the defined acceptance criteria. DOTA-MGS5, with confirmed affinity to the CCK2R, showed a high specific cell uptake and no interaction with other receptors in vitro when radiolabeled with gallium-68. Favorable in vivo properties were observed in biodistribution and dosimetry studies. An effective dose of similar to 0.01 mSv/MBq was estimated for humans utilizing OLINDA/EXM software. A maximum peptide dose of 50 mu g was established for the initial clinical dose based on the toxicity study in rats. The standardized production of [Ga-68]Ga-DOTA-MGS5 using an automated synthesis module and the performed non-clinical safety studies support a first exploratory clinical trial with this new PET imaging agent.

Automated summary

The new minigastrin analog DOTA-MGS5 shows promise for targeting CCK2R-expressing tumors, with extensive preclinical studies supporting its safety and efficacy for potential clinical translation. Using Ga-68-labeled DOTA-MGS5 for PET/CT imaging requires careful consideration of quality and safety aspects, with standardized production and non-clinical safety studies indicating suitability for exploratory clinical trials.