Noninvasive diagnostic imaging of tissues is essential for determining the identification and staging of diseases, and assessing the efficacy of treatment regimens. While most imaging methods provide structural information (CAT, X-Ray, MRI), positron emission tomography permits imaging of regions of specific biochemical activity. Positron emitting radiotracers may be designed to localize in specific tissue types, such as tumors, or they may give a measure of normal metabolic activity. The positron emitting nucleus 18F possesses an ideal half-life (110 minutes) and relatively short positron diffusion distance (1 mm);these features permit relatively high resolution images obtained from [18F]fluorinated radiotracers to be acquired rapidly, with little lingering radioactivity hazard for the patient. Unfortunately, preparation of many desirable [18F]fluoride-labeled radiotracers is stymied by the lack of highly efficient, broadly applicable aromatic radiofluorination methods. The goals of this research project are to develop general methodology to radiofluorinate electron rich aromatic rings with no-carrier-added (n.c.a.) [18F]fluoride and to facilitate general use of this methodology by developing chemistry that interfaces seamlessly with existing commercial automated radiotracer synthesis platforms. This wholly new capability will expand dramatically the types of diseases that can be imaged by PET, and will lead directly to innovative protocols for diagnostic imaging and tissue localization. The proposed research has three specific aims.
Specific aim 1 is to develop new, general, highly efficient methodology for single-step iodine-mediated radiofluorination of functionalized, electron-rich aromatic compounds with n.c.a. [18F]fluoride. The proposed work will build on a foundation of mechanistic studies describing the high yield formation of aryl fluorides from the reductive elimination of diaryliodonium fluoride salts.
Specific aim 2 is to develop a general synthetic methodology that permits highly functionalized aromatic compounds to be transformed into radiotracer precursors directly.
Specific aim 3 is to expand the scope of this synthetic chemistry by providing facile protecting group chemistry that is compatible with late stage radiofluorination of alkaloids.

Public Health Relevance

Noninvasive, in vivo imaging of biological processes is essential for identifying disease states and progression, and for assessing the efficacy of treatment regimens. This research will address the need for new positron emission tomography (PET) imaging agents by developing a novel methodology for their synthesis. The outcomes of this research program will be new diagnostic techniques to identify disease states and a general and facile means to access a wide variety of new and existing imaging agents;these compounds and procedures will provide the physician with new opportunities to probe, diagnose and assess human disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB015536-01
Application #
8348513
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Christina
Project Start
2012-07-01
Project End
2016-05-31
Budget Start
2012-07-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$316,073
Indirect Cost
$80,948
Name
University of Nebraska Lincoln
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588
Kothari, P; De, B P; He, B et al. (2017) Radioiodinated Capsids Facilitate In Vivo Non-Invasive Tracking of Adeno-Associated Gene Transfer Vectors. Sci Rep 7:39594
Linstad, Ethan J; V?vere, Amy L; Hu, Bao et al. (2017) Thermolysis and radiofluorination of diaryliodonium salts derived from anilines. Org Biomol Chem 15:2246-2252
Neumann, Kiel D; Qin, Linlin; V?vere, Amy L et al. (2016) Efficient automated syntheses of high specific activity 6-[18F]fluorodopamine using a diaryliodonium salt precursor. J Labelled Comp Radiopharm 59:30-4
Jiang, Huailei; DiMagno, Stephen G; DeGrado, Timothy R (2015) Production and Transport of Gaseous (18)F-Synthons: (18)F-Acyl Fluorides. J Fluor Chem 180:181-185
Qin, Linlin; Hu, Bao; Neumann, Kiel D et al. (2015) A Mild and General One-Pot Synthesis of Densely Functionalized Diaryliodonium Salts. European J Org Chem 2015:5919-5924
Hu, Bao; V?vere, Amy L; Neumann, Kiel D et al. (2015) A practical, automated synthesis of meta-[(18)F]fluorobenzylguanidine for clinical use. ACS Chem Neurosci 6:1870-9
Hu, Bao; Miller, William H; Neumann, Kiel D et al. (2015) An alternative to the Sandmeyer approach to aryl iodides. Chemistry 21:6394-8
Hu, Bao; DiMagno, Stephen G (2015) Reactivities of vinyl azides and their recent applications in nitrogen heterocycle synthesis. Org Biomol Chem 13:3844-55