Flow optimization study of a batch microfluidics PET tracer synthesizing device.

We present numerical modeling and experimental studies of flow optimization inside a batch microfluidic micro-reactor used for synthesis of human-scale doses of Positron Emission Tomography (PET) tracers. Novel techniques are used for mixing within, and eluting liquid out of, the coin-shaped reaction chamber. Numerical solutions of the general incompressible Navier Stokes equations along with time-dependent elution scalar field equation for the three dimensional coin-shaped geometry were obtained and validated using fluorescence imaging analysis techniques. Utilizing the approach presented in this work, we were able to identify optimized geometrical and operational conditions for the micro-reactor in the absence of radioactive material commonly used in PET related tracer production platforms as well as evaluate the designed and fabricated micro-reactor using numerical and experimental validations

Design and Optimization of Coin-Shaped Microreactor Chips for PET Radiopharmaceutical Synthesis

An integrated elastomeric microfluidic device, with a footprint the size of a postage stamp, has been designed and optimized for multistep radiosynthesis of PET tracers. Methods: The unique architecture of the device is centered around a 5-µL coin-shaped reactor, which yields reaction efficiency and speed from a combination of high reagent concentration, pressurized reactions, and rapid heat and mass transfer. Its novel features facilitate mixing, solvent exchange, and product collection. New mixing mechanisms assisted by vacuum, pressure, and chemical reactions are exploited. Results: The architecture of the reported reactor is the first that has allowed batch-mode microfluidic devices to produce radiopharmaceuticals of sufficient quality and quantity to be validated by in vivo imaging. Conclusion: The reactor has the potential to produce multiple human doses of ^(18)F-FDG; the most impact, however, is expected in the synthesis of PET radiopharmaceuticals that can be made only with low yields by currently available equipment

Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics

Microreactor technology has shown potential for optimizing synthetic efficiency, particularly in preparing sensitive compounds. We achieved the synthesis of an [^(18)F]fluoride-radiolabeled molecular imaging probe, 2-deoxy-2-[18F]fluoro-d-glucose ([^(18)F]FDG), in an integrated microfluidic device. Five sequential processes—[^(18)F]fluoride concentration, water evaporation, radiofluorination, solvent exchange, and hydrolytic deprotection—proceeded with high radio-chemical yield and purity and with shorter synthesis time relative to conventional automated synthesis. Multiple doses of [^(18)F]FDG for positron emission tomography imaging studies in mice were prepared. These results, which constitute a proof of principle for automated multistep syntheses at the nanogram to microgram scale, could be generalized to a range of radiolabeled substrates

Economical droplet-based microfluidic production of [18F]FET and [18F]Florbetaben suitable for human use.

Current equipment and methods for preparation of radiopharmaceuticals for positron emission tomography (PET) are expensive and best suited for large-scale multi-doses batches. Microfluidic radiosynthesizers have been shown to provide an economic approach to synthesize these compounds in smaller quantities, but can also be scaled to clinically-relevant levels. Batch microfluidic approaches, in particular, offer significant reduction in system size and reagent consumption. Here we show a simple and rapid technique to concentrate the radioisotope, prior to synthesis in a droplet-based radiosynthesizer, enabling production of clinically-relevant batches of [18F]FET and [18F]FBB. The synthesis was carried out with an automated synthesizer platform based on a disposable Teflon-silicon surface-tension trap chip. Up to 0.1 mL (4 GBq) of radioactivity was used per synthesis by drying cyclotron-produced aqueous [18F]fluoride in small increments directly inside the reaction site. Precursor solution (10 µL) was added to the dried [18F]fluoride, the reaction chip was heated for 5 min to perform radiofluorination, and then a deprotection step was performed with addition of acid solution and heating. The product was recovered in 80 µL volume and transferred to analytical HPLC for purification. Purified product was formulated via evaporation and resuspension or a micro-SPE formulation system. Quality control testing was performed on 3 sequential batches of each tracer. The method afforded production of up to 0.8 GBq of [18F]FET and [18F]FBB. Each production was completed within an hour. All batches passed quality control testing, confirming suitability for human use. In summary, we present a simple and efficient synthesis of clinically-relevant batches of [18F]FET and [18F]FBB using a microfluidic radiosynthesizer. This work demonstrates that the droplet-based micro-radiosynthesizer has a potential for batch-on-demand synthesis of 18F-labeled radiopharmaceuticals for human use

Flow optimization study of a batch microfluidics PET tracer synthesizing device.

We present numerical modeling and experimental studies of flow optimization inside a batch microfluidic micro-reactor used for synthesis of human-scale doses of Positron Emission Tomography (PET) tracers. Novel techniques are used for mixing within, and eluting liquid out of, the coin-shaped reaction chamber. Numerical solutions of the general incompressible Navier Stokes equations along with time-dependent elution scalar field equation for the three dimensional coin-shaped geometry were obtained and validated using fluorescence imaging analysis techniques. Utilizing the approach presented in this work, we were able to identify optimized geometrical and operational conditions for the micro-reactor in the absence of radioactive material commonly used in PET related tracer production platforms as well as evaluate the designed and fabricated micro-reactor using numerical and experimental validations

Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808.

Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have recently reported early clinical results of a novel PHF-tau targeting PET imaging agent, [F18]-T807. Since then, we have investigated a second novel PHF-tau targeting PET imaging agent, [F18]-T808, with different pharmacokinetic characteristics, which may be favorable for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F18]-T808

Early clinical PET imaging results with the novel PHF-tau radioligand [F18]-T808.

Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have recently reported early clinical results of a novel PHF-tau targeting PET imaging agent, [F18]-T807. Since then, we have investigated a second novel PHF-tau targeting PET imaging agent, [F18]-T808, with different pharmacokinetic characteristics, which may be favorable for imaging Alzheimer's disease and other tauopathies. Here, we describe the first human brain images with [F18]-T808