High-efficiency [18F]fluoride pre-concentration using a laser-micromachined anion-exchange micro-cartridge

Abstract

Background: The use of radiopharmaceuticals labelled with fluorine-18 in non-invasive imaging, particularly in Positron Emission Tomography (PET), increased significantly during the last decade. However, traditional nucleophilic fluorination synthesis methods in most cases require azeotropic drying steps, leading to loss of activity and increased synthesis time. Microfluidic devices offer improvements with shorter reaction times, higher elution efficiency, and reduced reagent quantities.

Results: We developed a novel micro-cartridge for [¹⁸F]fluoride trapping and elution, etched in borosilicate optical glass (BK7) using ultrashort laser pulse machining. The micro-cartridge has a bead volume of 17 µL and a maximum capacity of 8.5 mg for anion exchange resin. The micro-cartridge, without the need for QMA preconditioning, exhibited an overall trapping efficiency and recovery efficiency (RE) of (94.09 ± 0.12)% using an activity exceeding 123 GBq of [¹⁸F]fluoride. This RE was obtained using 100 µL of a standard solution of anhydrous acetonitrile with Kryptofix 2.2.2, containing only 5 µL of water and 5.4 µmol of K₂CO₃ for [¹⁸F]fluoride elution. This solution was employed directly in the radiosynthesis of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO), resulting in a 100% radiochemical conversion (RCC) to THP-protected [¹⁸F]FMISO within 10 min at 110 °C.

Conclusions: The developed micro-cartridge provides a novel tool for integrating microfluidic chips into conventional cassettes, facilitating more efficient radiopharmaceutical preparation.

Keywords: Micro-cartridge; Microfluidics; Positron emission tomography (PET); Ultra-short laser pulse; [18F]fluoride.

Fig. 1

Scheme Flowchart of [¹⁸F]FMISO radiopharmaceutical synthesis

Fig. 2

a Photograph of the laser machined micro-cartridge; b Micrography of the micropillars; c Detailed profilometry of the micropillar structures showing wall inclination angles (Ang) and depth (Rdz)

Fig. 3

a Representation of the sequence of the complete assembly of the micro cartridge; b Acrylic mask used to assist in packing the QMA resin; c Pre-assembly of the micro-cartridge for determination of the mass of QMA in the reservoir, always with the same screws in the same position; d Final assembly of the micro-cartridge with all the screws to form a watertight seal and the support used in the experiments

Fig. 4

HPLC analysis of THP-protected [¹⁸F]FMISO with UV detection channel installed in front of the radioactivity detector: a Radioactivity detector TPH-protected [¹⁸F]FMISO (Rt = 11.9 min); b UV channel analysis of THP-protected [¹⁸F]FMISO c  UV analysis for the NITTP standard precursor (Rt = 15.1 min Supplementary Fig. S9 and Table S5)

Fig. 5

HPLC analysis [¹⁸F]FMISO: a Before purification, [¹⁸F]FMISO (Rt = 7.0 min) showed an area of ~ 81%, while [¹⁸F]fluorine (Rt = 3.3 min) showed an area of ~ 19% (Supplementary Fig. S10 and Table S6); b After purification of [¹⁸F]FMISO (Rt = 7.1 min); c UV detector for the [¹⁹F]FMISO standard (Rt = 6.9 min)