Good practices for 68Ga radiopharmaceutical production

Abstract

Background: The radiometal gallium-68 (⁶⁸Ga) is increasingly used in diagnostic positron emission tomography (PET), with ⁶⁸Ga-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional ^99mTc agents. In precision medicine, PET applications of ⁶⁸Ga are widespread, with ⁶⁸Ga radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin.

Main body: These ⁶⁸Ga radiopharmaceuticals include agents such as [⁶⁸Ga]Ga-macroaggregated albumin for myocardial perfusion evaluation, [⁶⁸Ga]Ga-PLED for assessing renal function, [⁶⁸Ga]Ga-t-butyl-HBED for assessing liver function, and [⁶⁸Ga]Ga-PSMA for tumor imaging. The short half-life, favourable nuclear decay properties, ease of radiolabeling, and convenient availability through germanium-68 (⁶⁸Ge) generators and cyclotron production routes strongly positions ⁶⁸Ga for continued growth in clinical deployment. This progress motivates the development of a set of common guidelines and standards for the ⁶⁸Ga radiopharmaceutical community, and recommendations for centers interested in establishing ⁶⁸Ga radiopharmaceutical production.

Conclusion: This review outlines important aspects of ⁶⁸Ga radiopharmacy, including ⁶⁸Ga production routes using a ⁶⁸Ge/⁶⁸Ga generator or medical cyclotron, standardized ⁶⁸Ga radiolabeling methods, quality control procedures for clinical ⁶⁸Ga radiopharmaceuticals, and suggested best practices for centers with established or upcoming ⁶⁸Ga radiopharmaceutical production. Finally, an outlook on ⁶⁸Ga radiopharmaceuticals is presented to highlight potential challenges and opportunities facing the community.

Keywords: 68Ga-radiolabeling; 68Ga-tracer; Automation; Cyclotron; Gallium-68; Radiolabeling; Radiopharmaceuticals.

Fig. 1

Structures of several ⁶⁸Ga radiopharmaceuticals in clinical use (1) PSMA-11 (Fuscaldi et al.; Hennrich and Eder 2021) (2) PentixaFor (Sammartano et al. ; Spreckelmeyer et al. 2020) (3) FAPI-46 (Spreckelmeyer et al. 2020) (4) R = H DOTA-TOC (Bauwens et al. ; Decristoforo et al. 2007); R = Carbonyl DOTA-TATE (5) Exendin peptide sequence = HGEGTFTSDL SKQ M EEEAVR LFIEWLKNGG PSSGAPPPS C = Exendin-4-Cys40(DOTA) (Velikyan et al. 2017) (6) Exendin peptide sequence = HGEGTFTSDL SKQ M EEEAVR LFIEWLKNGG PSSGAPPPS K = Exendin-4-Lys40(NODAGA) (Velikyan et al. ; Migliari et al. 2021)

Fig. 2

The four main steps of the ⁶⁸Ga-radiolabeling procedure (Meisenheimer et al. 2019)

Fig. 3

Schematic overview of automated radiolabeling process

Fig. 4

Possible geometric isomers for hexadentate [Ga(HBED)] (Tsionou et al. , 2017)

Fig. 5

Radio-HPLC chromatogram of 68Ga-DOTA-TATE with the addition of 10% sodium thiosulfate (Left) and with the addition of 10% ethanol (Right) (Mu et al. 2013)