Automated microfluidic-based production of PET radioligands for clinical and preclinical use

In recent decades, microfluidic technologies have been explored for PET radiopharmaceutical production. Moreover, radiotracer production models have been gradually transitioning from centralized to decentralized models using custom microfluidic modules. This project aimed to introduce iMiDEVTM, an automated microfluidic synthesis module for the production of radiopharmaceuticals, and to enable dose-on-demand (DOD) or single-dose production based on clinical and preclinical needs.

The work done in Paper I introduces the iMiDEV™ microfluidic system, a novel cassette-based automated module designed for the small-scale production of radiopharmaceuticals. This radiochemistry module uses a microfluidic cassette to perform liquid-phase reactions in an automated synthesizer. The user-friendly interface allows for manual and fully automated operations, facilitating efficient synthesis processes.

Building on the foundation laid by the work in Paper I, Paper II explores the application of microfluidic techniques in PET radiopharmaceutical synthesis. Specifically, we investigated the use of an iMiDEVTM radiosynthesizer with a microfluidic cassette to produce [11C]flumazenil and L-[ 11C]deprenyl. Through meticulous method development and prep-HPLC integration, Paper II achieved good radiochemical yields (RCYs) and purities for both radiotracers with high molar activity, thus demonstrating the efficacy of the microfluidic synthesis methods.

Paper III work concentrated on the production of increasingly demanding 68Ga labeled tracers and emphasized the vital role of microfluidic technology in meeting this rising demand. Specifically, [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA TOC were synthesized as crucial tracers in theranostic applications. Through the fine-tuning of multiple parameters, such as 68Ga elution, mixing techniques, and purification methods, this study achieved good RCYs and purities by utilizing 3-5 times less precursor. This achievement highlights the potential of microfluidic based approaches in clinical settings and has been further validated by testing the developed methods in a separate radiochemistry laboratory setting, which has achieved comparable results.

Using microfluidic cassettes and the iMiDEV™ module, Paper IV showcases the synthesis of radiotracers, including L-[ 11C]methionine and [11C]choline. By carefully optimizing the precursor amounts and synthesis parameters, high RCYs and purity levels were successfully achieved, confirming the viability of the DOD synthesis approach for clinical applications.

This project highlights the transformative impact of microfluidic technology on PET radiopharmaceutical synthesis. By enabling automated, versatile, and efficient synthetic processes along with the DOD approach, microfluidic-based approaches hold promise in advancing research and clinical applications in nuclear medicine.

List of scientific papers

I. Ovdiichuk, O.; Mallapura, H.; Pineda, F.; Hourtané, V.; Långström, B.; Halldin, C.; Nag, S.; Maskali, F.; Karcher, G.; Collet, C. Implementation of iMiDEV™, a new fully automated microfluidic platform for radiopharmaceutical production. Lab Chip. 2021, 21, 2272-2282.
https://doi.org/10.1039/d1lc00148e

II. Mallapura, H.; Tanguy, L.; Långström, B.; Meunier, L.L.; Halldin, C.; Nag, S. Production of [11C]Carbon Labelled Flumazenil and L-Deprenyl Using the iMiDEV™ Automated Microfluidic Radiosynthesizer. Molecules. 2022, 27.
https://doi.org/10.3390/molecules27248843

III. Mallapura, H.; Ovdiichuk, O.; Jussing, E.; Thuy, T.A.; Piatkowski, C.; Tanguy, L.; Collet-Defossez, C.; Långström, B.; Halldin, C.; Nag, S. Microfluidic-based production of [68Ga]Ga-FAPI-46 and [68Ga]Ga DOTA-TOC using the cassette-based iMiDEV™ microfluidic radiosynthesizer. EJNMMI Radiopharmacy and Chemistry. 2023, 8, 42.
https://doi.org/10.1186/s41181-023-00229-9

IV. Mallapura, H.; Tanguy, L.; Mahfuz, S.; Bylund, L.; Långström, B.; Halldin, C.; Nag, S. Advancements in Microfluidic Cassette-Based iMiDEV™ Technology for Production of L-[11C]Methionine and [11C]Choline. Pharmaceuticals. 2024, 17, 250.
https://doi.org/10.3390/ph17020250