Summary
UCLA researchers in the Department of Pharmacology have developed a novel aromatic nucleophilic fluorination reaction producing Fluorine-18 [F-18]-labeled aromatic compounds with extensive use in Positron Emission Tomography (PET).
Background
Positron Emission Tomography (PET or PET scan) is an imaging technique that is used to observe metabolic processes in the body. PET detects gamma rays emitted by a positron-emitting radioactive probe, also known as radionuclide, which is introduced into the body on a biologically active molecule. In the case of [F-18] flurodeoxyglucose, a glucose analog, the concentrations of [F-18] flurodeoxyglucose imaged indicate tissue metabolic activity as it corresponds to the regional glucose uptake. Three-dimensional images of the [F-18] flurodeoxyglucose concentration within the body are then constructed to exam tumors and search for cancer metastasis in clinical oncology. PET is also an important tool to map brain and heart function, and a research tool for drug development. Incorporation of positron emitting fluorine-18 into aromatic ring systems (i.e. glucose) plays an important role in developing new probes for utilization with PET. Electrophilic and nucleophilic fluorine substitution reactions are two major pathways commonly used for this process. Electrophilic fluorination reactions provide products with low specific activities because of the unavoidable addition of non-radioactive carrier fluorine during the production of F-18 labeled fluorine. Low specific activity radionuclides are generally useful for monitoring enzyme-mediated processes, but they are unsuitable for investigation of biochemical processes, which involve stoichiometric binding interactions. In contrast, nucleophilic fluorination reactions generate radionuclides with high specific activity. Facile displacement of certain leaving groups (i.e. nitro and quaternary ammonium moiety) in aromatic compounds activated by electron withdrawing substituents provides 30-80% radiochemical yields. However, nitroaromatics (reactant) and fluoroaromatics (product) have very similar chromatographic properties and are difficult to separate, whereas quaternary ammonium group substituted aromatics (reactant) are difficult to synthesize. In addition, as the complexity of the aromatic ring system increases, as is the case with almost all the useful probes, the radiochemical yields drops drastically. Furthermore, aromatic compounds lacking electron withdrawing/deactivating substituents often fail to undergo this reaction. Therefore, there is a great need for nucleophilic aromatic fluorination reaction conditions that are suitable for the preparation of F-18 labeled radionuclide having a variety of substituents. Availability of such methods will enable an easy access to large groups of molecular imaging probes for PET.
Innovation
Researchers at UCLA have developed a new fluorination reaction scheme, which utilizes the reaction of phenyl iodonium ylides with no carrier added F-18 fluoride ion. The average radiochemical yield of the described nucleophilic fluorination reaction is much higher than currently used methods.
Applications
Production of F-18 labeled radionuclide that have a variety of substituents for PET scan.
Advantages
Comparing to nitroaromatics and quaternary ammonium group substituted aromatics, the iodonium ylide derivatives are relatively easy to prepare, and the fluoroaryl products obtained are also easy to purify.
State Of Development
The fluorination reaction has been tested with several unsubstituted and substituted phenyl iodonium ylides.