Microfluidic-based production of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC using the cassette-based iMiDEV™ microfluidic radiosynthesizer

Hemantha Mallapura; Olga Ovdiichuk; Emma Jussing; Tran A Thuy; Camille Piatkowski; Laurent Tanguy; Charlotte Collet-Defossez; Bengt Långström; Christer Halldin; Sangram Nag

doi:10.1186/s41181-023-00229-9

Microfluidic-based production of [⁶⁸Ga]Ga-FAPI-46 and [⁶⁸Ga]Ga-DOTA-TOC using the cassette-based iMiDEV™ microfluidic radiosynthesizer

EJNMMI Radiopharm Chem. 2023 Dec 13;8(1):42. doi: 10.1186/s41181-023-00229-9.

Authors

Hemantha Mallapura¹, Olga Ovdiichuk², Emma Jussing^{3

4}, Tran A Thuy^{3

4}, Camille Piatkowski⁵, Laurent Tanguy⁵, Charlotte Collet-Defossez^{2

6}, Bengt Långström⁷, Christer Halldin⁸, Sangram Nag⁸

Affiliations

¹ Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-17176, Stockholm, Sweden. hemantha.mallapura@ki.se.
² Nancyclotep, Molecular Imaging Platform, 5 Rue du Morvan, 54500, Vandoeuvre Les Nancy, France.
³ Department of Oncology and Pathology, Karolinska Institutet, 17177, Stockholm, Sweden.
⁴ Department of Radiopharmacy, Karolinska University Hospital, 17176, Stockholm, Sweden.
⁵ PMB-Alcen, Route des Michels CD56, 13790, Peynier, France.
⁶ Inserm, IADI, Université de Lorraine, 54000, Nancy, France.
⁷ Department of Chemistry, Uppsala University, 75123, Uppsala, Sweden.
⁸ Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, SE-17176, Stockholm, Sweden.

Abstract

Background: The demand for ⁶⁸Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, ⁶⁸Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([⁶⁸Ga]Ga-FAPI-46) in late-phase studies, whereas [⁶⁸Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [⁶⁸Ga]Ga-FAPI-46 and [⁶⁸Ga]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach.

Results: Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 ± 5% for [⁶⁸Ga]Ga-FAPI-46 and 46 ± 7% for [⁶⁸Ga]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [⁶⁸Ga]Ga-FAPI-46 and [⁶⁸Ga]Ga-DOTA-TOC were 98.2 ± 0.2% and 98.4 ± 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including ⁶⁸Ga trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers.

Conclusions: The microfluidic-based approach enabled the implementation of radiosynthesis of [⁶⁸Ga]Ga-FAPI-46 and [⁶⁸Ga]Ga-DOTA-TOC on the iMiDEV™ microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2-3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [⁶⁸Ga]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.

Keywords: Dose-on-demand (DOD); Microfluidics; Positron emission tomography (PET); Radiolabeling; Radiopharmaceuticals; Radiotracers; [68Ga]Ga-DOTA-TOC; [68Ga]Ga-FAPI-46; iMiDEV.