Positron emission tomography (PET) is a molecular imaging modality that utilizes radiolabeled probe molecules to target, image and quantify biological processes in vivo. PET probes can be used to study disease mechanisms, to develop novel diagnostics and therapeutics, detect early stage disease, and monitor response to therapy. Due to the high cost of equipment, infrastructure, and personnel currently required to produce PET probes, the availability and diversity of probes is severely limited (especially for research purposes), hindering both research that depends on this imaging tool and the translation of novel PET probes into medical practice. This challenge is being addressed by efforts to develop miniaturized PET probe production technology based on microfluidics with the eventual goal of an affordable, automated, user-friendly system with built-in radiation shielding that operates on a bench top instead of in a """"""""hot cell"""""""". Such a system would enable on-demand production of diverse probes at affordable cost. Current miniaturization efforts have focused primarily on the synthesis itself, and not on downstream processes such as purification and formulation. Most PET tracers require a concentration process during formulation to reduce the volume after HPLC purification so that a sufficient amount of probe is contained in the limited volume that can be injected into small animal models such as mice without adversely affecting their physiology. Concentration is currently achieved by rotary evaporation, using bulky equipment occupying valuable real estate inside the hot cell. To prevent the concentrator from becoming the size-limiting factor in miniaturized radio synthesis, there is a need for development of miniature concentration technologies. In preliminary studies, a compact proof-of-concept microfluidic device to evaporatively concentrate aqueous solutions was developed, and successful concentration of the PET probe 1-(2'-deoxy-2'-[18F]fluoro- arabinofuranosyl) cytosine ([18F]FAC) dissolved in 1:99 EtOH : 10mM NH4H2PO4 (HPLC mobile phase) was demonstrated. This proof-of-concept chip will be further developed in this application into a robust, automated, compact system for routinely concentrating diverse probes.
Aim 1 focuses on the development of a microfluidic chip with performance increased to at least match that typically achieved by rotary evaporation.
In Aim 2, the chip parameters and operating conditions will be characterized to enable further performance optimization. The concentrated sample collection process will be optimized in Aim 3.
In Aim 4, an upstream module will be developed to enable concentration of non-aqueous solutions, thereby extending this technology to all PET probes. A fully automated system (sample loading, concentration, and recovery) will be developed in Aim 5. This application will result in the development of a prototype microfluidic concentrator that will be a critical part of emerging benchtop production platforms for diverse PET probes that will accelerate preclinical research and translation of diagnostics and therapies to the clinic by increasing access to molecular imaging with PET.

Public Health Relevance

The proposed research will provide an inexpensive, compact technology for concentrating PET probes after their synthesis and HPLC purification. This critical step of PET probe production is necessary to ensure sufficient amount of the probe is contained within the limited volume that can be injected into animal models in preclinical cancer research toward new diagnostics and therapies and increased understanding of the causes and mechanisms of disease. Forming an integral part of a complete benchtop solution for PET probe production, the proposed technology will accelerate research by driving down costs of, and increasing access to, multitudes of PET probes currently unavailable to most researchers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1)
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Ossandon, Miguel
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Collins, Jeffrey; Waldmann, Christopher M; Drake, Christopher et al. (2017) Production of diverse PET probes with limited resources: 24 18F-labeled compounds prepared with a single radiosynthesizer. Proc Natl Acad Sci U S A 114:11309-11314
Chao, Philip H; Collins, Jeffery; Argus, Joseph P et al. (2017) Automatic concentration and reformulation of PET tracers via microfluidic membrane distillation. Lab Chip 17:1802-1816
Tseng, Wei-Yu; van Dam, R Michael (2014) Compact microfluidic device for rapid concentration of PET tracers. Lab Chip 14:2293-302