title: Batch-reactor microfluidic device: first human use of a microfluidically produced PET radiotracer.
abstract: The very first microfluidic device used for the production of (18)F-labeled tracers for clinical research is reported along with the first human Positron Emission Tomography scan obtained with a microfluidically produced radiotracer. The system integrates all operations necessary for the transformation of [(18)F]fluoride in irradiated cyclotron target water to a dose of radiopharmaceutical suitable for use in clinical research. The key microfluidic technologies developed for the device are a fluoride concentration system and a microfluidic batch reactor assembly. Concentration of fluoride was achieved by means of absorption of the fluoride anion on a micro ion-exchange column (5 μL of resin) followed by release of the radioactivity with 45 μL of the release solution (95 ± 3% overall efficiency). The reactor assembly includes an injection-molded reactor chip and a transparent machined lid press-fitted together. The resulting 50 μL cavity has a unique shape designed to minimize losses of liquid during reactor filling and liquid evaporation. The cavity has 8 ports for gases and liquids, each equipped with a 2-way on-chip mechanical valve rated for pressure up to 20.68 bar (300 psi). The temperature is controlled by a thermoelectric heater capable of heating the reactor up to 180 °C from RT in 150 s. A camera captures live video of the processes in the reactor. HPLC-based purification and reformulation units are also integrated in the device. The system is based on "split-box architecture", with reagents loaded from outside of the radiation shielding. It can be installed either in a standard hot cell, or as a self-shielded unit. Along with a high level of integration and automation, split-box architecture allowed for multiple production runs without the user being exposed to radiation fields. The system was used to support clinical trials of [(18)F]fallypride, a neuroimaging radiopharmaceutical under IND Application #109,880.
authors.affiliation: Molecular Imaging Biomarker Research, Siemens Healthcare, 6100 Bristol Pkw, Culver City, California, USA. artem.lebedev@siemens.com
authors.forename: Artem
authors.initials: A
authors.lastname: Lebedev
authors.forename: Reza
authors.initials: R
authors.lastname: Miraghaie
authors.forename: Kishore
authors.initials: K
authors.lastname: Kotta
authors.forename: Carroll E
authors.initials: CE
authors.lastname: Ball
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Monte S
authors.initials: MS
authors.lastname: Buchsbaum
authors.forename: Hartmuth C
authors.initials: HC
authors.lastname: Kolb
authors.forename: Arkadij
authors.initials: A
authors.lastname: Elizarov
mesh_terms: D001549:Benzamides / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid; D004867:Equipment Design; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D006801:Humans; D046210:Microfluidic Analytical Techniques / Q000295:instrumentation* / Q000379:methods*; D049268:Positron-Emission Tomography / Q000295:instrumentation / Q000379:methods*; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D012984:Software; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; D019275:Radiopharmaceuticals; C574003:fallypride