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. 2025;18(4):302-317.
doi: 10.2174/0118744710379515250506045145.

[68Ga]Ga-DOTA-TOC Synthesis by a Cassette Developer System with [68Ga]GaCl3 from Cyclotron using Liquid Target: An Italian Experience

Michela Cossandi  1 , Massimo Statuto  1 , Giorgio Biasiotto  2 , Gian Luca Vigano  3 , Luca Camoni  4 , Elena Migliorati  1 , Carlo Rodella  5 , Federica Saiani  5 , Luigi Spiazzi  5 , Francesco Bertagna  4
Affiliations

[68Ga]Ga-DOTA-TOC Synthesis by a Cassette Developer System with [68Ga]GaCl3 from Cyclotron using Liquid Target: An Italian Experience

Michela Cossandi et al. Curr Radiopharm. 2025.

Abstract

Introduction: [68Ga-DOTA-D-Phe1-Tyr3]octreotide ([68Ga]Ga-DOTA-TOC) is a somatostatin analogue largely used in PET/CT applications for the detection of gastroenteropancreatic neuroendocrine tumors (GEP-NET). Initially, it was obtained using a 68Ge/68Ga generator. The increasing cost of good manufacturing practice-compliant generators has led to the need to find alternative ways of producing Gallium-68 (68Ga). The aim of this work is to show the production optimization of [68Ga]Ga-DOTA-TOC via cyclotron, derived from three years of experience.

Methods: The production of [68Ga]GaCl3 via the 68Zn(p,n)68Ga reaction was optimized using a PETtrace 800 cyclotron (equipped with ZnO liquid target) and the synthesis of [68Ga]Ga- DOTA-TOC was performed by FASTlab2 developer system according to the Guidelines on Good Radiopharmacy Practice (cGRPP). Quality control process was validated according to the current specific monograph (2482) of the European Pharmacopoeia (Ph. Eur.).

Results: [68Ga]Ga-DOTA-TOC was produced in 40 minutes; ten validation batches met the quality criteria expected by the Ph. Eur. The synthesis process has involved many issues due to the use of acidic reagents and related corrosion of some components of cyclotron and developer system, resulting in 12.2% failed syntheses and a target breakdown after 11 months.

Discussion: The main issues, their causes and the strategies used to solve them are reported in the troubleshooting section: thanks to these strategies, the number of failed syntheses has decreased, and today, we have achieved a 0% failure rate.

Conclusion: Liquid target production of [68Ga]Ga-DOTA-TOC, once consolidated, instead of 68Ge/68Ga generator has many advantages.

Keywords: Cyclotron; [68Ga]Ga-DOTA-TOC; european pharmacopeia.; gastroenteropancreatic neuroendocrine tumors; generator; liquid target; positron emission tomography; radiopharmaceutical.

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Conflict of interest statement

Francesco Bertagna is on the Editorial Advisory Board of the journal CRP.

Figures

Fig. (1)
Fig. (1)
[68Ga]Ga-DOTATOC: in green the chelator DOTA, in red Gallium-68 isotope and in black the structure of edotreotide (peptide) in which there is in position 3 a Tyrosine instead of a Phenilalanine. (https://www.mdpi.com/1424-8247/13/3/38).
Fig. (2)
Fig. (2)
(A) Cassette developer system, in particular: (A1) External receiving vial Taddeo, (A2) Zn recovery vial, (A3) Product vial; (B) synthesis cassette: the highlighted part on the right (B2) contains the reagents and cartridges for the purification of [68Ga]GaCl3, while the highlighted part on the left (B1) contains the reagents for the production of [68Ga]Ga-DOTATOC.
Fig. (3)
Fig. (3)
The figure shows the profile of measure of Reference solution verified by isocratic HPLC-Ultimate 3000: 50 mg·V−1 Ga-edotreotide and 60 mg·V−1 edotreotide.
Fig. (4)
Fig. (4)
The figures show the profiles of measures obtained by isocratict HPLC-Ultimate 3000, in particular: on the left [68Ga]Ga-DOTATOC analized with a radioactivity detector; on the right [68Ga]Ga-DOTATOC analized with UV detector.
Fig. (5)
Fig. (5)
68Ga Liquid Target (on the left); use of acids damaged components of gallium liquid target (foils in the figure on the right).
Fig. (6)
Fig. (6)
Damaged components of the synthesis module: (A) Valve actuators; (A1) Valve actuators corroded by acids used for [68Ga]GaCl3 purification (HCl, HNO3). (B) Vacuum pump; (B1 and B2) Particular of vacuum pump in which are visible (red arrows) precipitates due to evaporation of HNO3.
See this image and copyright information in PMC

References

    1. Cives M., Strosberg J.R. Gastroenteropancreatic neuroendocrine tumors. CA Cancer J. Clin. 2018;68(6):471–487. doi: 10.3322/caac.21493. - DOI - PubMed
    1. Evangelista L., Ravelli I., Bignotto A., Cecchin D., Zucchetta P. Ga-68 DOTA-peptides and F-18 FDG PET/CT in patients with neuroendocrine tumor: A review. Clin. Imaging. 2020;67:113–116. doi: 10.1016/j.clinimag.2020.05.035. - DOI - PubMed
    1. Kandathil A., Subramaniam R.M. Gastroenteropancreatic neuroendocrine tumor diagnosis. PET Clin. 2023;18(2):189–200. doi: 10.1016/j.cpet.2022.11.001. - DOI - PubMed
    1. Lugat A., Frampas É., Touchefeu Y., Mirallié É., Bras M.L., Senellart H., Rauscher A., Fleury V., Campion L., Rohmer V., Couturier O.F., Lebtahi R., Rouzet F., Ruszniewski P., Kraeber-Bodéré F., Bourgeois M., Ansquer C. Prospective multicentric assessment of 68Ga-DOTANOC PET/CT in grade 1-2 GEP-NET. Cancers. 2023;15(2):513. doi: 10.3390/cancers15020513. - DOI - PMC - PubMed
    1. Database of the national nuclear data center (NNDC) at brookhaven national laboratory. Available from: www.nndc.bnl.gov/nndc/nudat/radform.html.

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