This Small Business Innovation Research Phase I project will support a new synthetic chemical approach for the creation of positron emission tomography (PET) imaging products to manage neurodegenerative disorders, cancer, and cardiovascular disease. Creating these imaging products relies on the rapid and efficient labeling of tracer molecules with a radioisotope ([18F]fluoride). The difficulties inherent in radiofluorination chemistry have severely limited the scope of radiotracers available for clinical use. This NSF SBIR Phase 1 project addresses this critical problem using the company?s proprietary single-step fluorination technology. This technology advances the current state-of-the-art with simple, fast, and highly efficient radiofluorination, permitting an entire new class of drugs to be labeled with no-carrier-added [18F]fluoride for the first time. The project will focus on the synthesis of clinically relevant radiotracers for pediatric cancer and Parkinson?s disease. Technical studies to be performed using this support include optimization of this new radiofluorination manufacturing methodology across multiple radiosynthesis platforms.
The broader impact/commercial potential of this project is to provide technology to expand the scope of PET as a platform for determining the identification and staging of diseases, and assessing the efficacy of treatment regimens. PET is an underutilized diagnostic imaging technique that is stymied by the lack of highly efficient, broadly applicable radiofluorination methods. The radiotracer manufacturing technology developed here is extremely general and applicable to the preparation of new imaging agents for PET. The availability of this general labeling technique can also speed development of new drugs by providing in vivo biomarkers of new therapeutic agents which can be used to determine optimal dosing of new drugs and variability of biodistribution in target populations. The commercial potential of PET imaging is significant; the worldwide market for PET is expected to grow to $15 billion by 2015. There is also room for significant expansion of this market as new imaging agents become available.
Under this NSF SBIR Phase 1 Award, Ground Fluor Pharmaceuticals, Inc. (GFP) of Lincoln, Nebraska developed and applied new methods for the synthesis of [18F]-fluorinated radiotracers. These compounds are useful for noninvasive imaging of cancer and neurological disorders by positron emission tomography (PET). Underlying the Intellectual Merit of this science is that a wide range of potentially valuable [18F]-fluorinated imaging agents are not accessible using current synthetic methodology. Because of its short half-life (109.7 minutes), [18F]-fluoride must be generated, incorporated into an imaging molecule, and used for imaging within a few hours. GFP has proprietary fluorine labeling technology (SWIFT®) that permits the radioactive isotope to be introduced into aromatic compounds rapidly, directly and efficiently. Under this award, SWIFT® technology was employed to develop a reliable synthesis of [18F]-6-fluoro-3,4-dihydroxy-L-phenylalanine, or [18F]FDOPA, a compound with proven utility in cancer and brain imaging, but one that is difficult to obtain in high specific activity. Key activities during this award were testing the radiosynthesis of [18F]FDOPA in partner academic and commercial laboratories, producing a second generation of the precursor material to simplify the synthesis and make it compatible with a wider range of commercially available radiotracer synthesis modules, and optimizing the SWIFT® procedure using this new precursor and new synthesis modules. Key findings from this work include: (1) High specific activity (SA > 4 Ci/umol) [18F]FDOPA can now be prepared in > 35% yield in 45 minutes using commercially available radiotracer synthesis modules such as the GE Tracerlab FX FN or the Synthera V1. (2) GFP’s [18F]FDOPA was used successfully in a variety of imaging studies, which confirmed the expected biodistribution of the tracer. For example, [18F]FDOPA localized and allowed imaging of a human colon cancer implanted into a mouse. (3) A new precursor (ALPDOPA®) was developed that permits the synthesis to be performed using very mild deprotection chemistry. This advance makes the SWIFT® procedure more amenable to wide spread implementation by radiopharmacies. (4) Revised, cassette-friendly reaction conditions now permit this process to be carried out in an expanded range of automated synthesizers. In addition to having a significant economic impact in Lincoln, NE, the project also resulted in the professional training of two GFP employees in organic synthesis and radiochemistry, and involved collaborations with three leading academic hospitals. The Broader Impacts of involving these institutions and teaching them to use the extremely versatile SWIFT® technology are that the range of new imaging agents that can be synthesized efficiently is expanded, and that the process is tested for commercial viability. Ultimately, the commercial availability of tracers such as [18F]FDOPA should have a positive impact on the diagnosis and treatment of serious human diseases.
