⁶⁸Ga-Radiolabeling and Pharmacological Characterization of a Kit-Based Formulation of the Gastrin-Releasing Peptide Receptor (GRP-R) Antagonist RM2 for Convenient Preparation of [⁶⁸Ga]Ga-RM2

• Main Authors: Adrien Chastel (Author), Delphine Vimont (Author), Stephane Claverol (Author), Marion Zerna (Author), Sacha Bodin (Author), Mathias Berndt (Author), Stéphane Chaignepain (Author), Elif Hindié (Author), Clément Morgat (Author)
• Format: Knjiga
• Izdano: MDPI AG, 2021-07-01T00:00:00Z.
• Teme: article
• Online dostop: Connect to this object online.

Izvleček

Background: [⁶⁸Ga]Ga-RM2 is a potent Gastrin-Releasing Peptide-receptor (GRP-R) antagonist for imaging prostate cancer and breast cancer, currently under clinical evaluation in several specialized centers around the world. Targeted radionuclide therapy of GRP-R-expressing tumors is also being investigated. We here report the characteristics of a kit-based formulation of RM2 that should ease the development of GRP-R imaging and make it available to more institutions and patients. Methods: Stability of the investigated kits over one year was determined using LC/MS/MS and UV-HPLC. Direct ⁶⁸Ga-radiolabeling was optimized with respect to buffer (pH), temperature, reaction time and shaking time. Conventionally prepared [⁶⁸Ga]Ga-RM2 using an automated synthesizer was used as a comparator. Finally, the [⁶⁸Ga]Ga-RM2 product was assessed with regards to hydrophilicity, affinity, internalization, membrane bound fraction, calcium mobilization assay and efflux, which is a valuable addition to the in vivo literature. Results: The kit-based formulation, kept between 2 °C and 8 °C, was stable for over one year. Using acetate buffer pH 3.0 in 2.5-5.1 mL total volume, heating at 100 °C during 10 min and cooling down for 5 min, the [⁶⁸Ga]Ga-RM2 produced by kit complies with the requirements of the European Pharmacopoeia. Compared with the module production route, the [⁶⁸Ga]Ga-RM2 produced by kit was faster, displayed higher yields, higher volumetric activity and was devoid of ethanol. In in vitro evaluations, the [⁶⁸Ga]Ga-RM2 displayed sub-nanomolar affinity (K<i>_d</i> = 0.25 ± 0.19 nM), receptor specific and time dependent membrane-bound fraction of 42.0 ± 5.1% at 60 min and GRP-R mediated internalization of 24.4 ± 4.3% at 30 min. The [^natGa]Ga-RM2 was ineffective in stimulating intracellular calcium mobilization. Finally, the efflux of the internalized activity was 64.3 ± 6.5% at 5 min. Conclusion: The kit-based formulation of RM2 is suitable to disseminate GRP-R imaging and therapy to distant hospitals without complex radiochemistry equipment.

Opis knjige/članka

10.3390/pharmaceutics13081160
1999-4923