Novel strategies for fluorine-18 radiochemistry.

Positron (b) emission tomography (PET) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiological structures and processes. PET imaging involves the incorporation of short-lived radionuclides, particularly carbon-11 and fluorine-18, into biologically active molecules. The resulting radiopharmaceuticals are introduced into human subjects, liberating positrons in the decay process that subsequently annihilate with electrons in adjacent matter. Detection of the g radiation generated during annihilation allows for well-defined images of ongoing bodily processes to be obtained. Understandably, wielding this technology— which requires the manipulation of strong radioemitters, short end-product efficacy timeframes, and rigorous quality control—is not a simple undertaking. In answer to this, and speaking to its clinical value, research pertaining to PET has observed exciting and rapid growth. The prospective applications for PET imaging are innumerable. Exploiting PET to its fullest potential has been limited, however, in large part, by the availability of pertinent radiopharmaceuticals. The identification of a suitable radionuclide for use in labeling is a concern intrinsic to the preparation of radiopharmaceutical agents. Carbon-11 and fluorine-18 are commonly used and each has its own merits. Radiolabeling with C has advantages that include minimal effects on substrate biological activity and ease of incorporation. C-radiolabeling also affords the ability to run multiple scans per day in series. However, C suffers from a rather short half-life (20 min) and susceptibility to environmental C contamination in processing. F finds utility in light of the fact that its incorporation into bioactive species sometimes affects their pharmacological profile. Fluorine-18 offers the benefit of a substantial half-life (about 110 min, allowing for distribution to satellite PET scan facilities), a clean decay process (97% b emission) and limited positron migration (about 1 mm, leading to highly resolved images). Indeed, F is ubiquitous in molecular imaging by positron emission tomography, as is exemplified by the success of [F]2-fluoro2-deoxy-d-glucose (FDG) in oncology research. [F]Fluoride is prepared by the proton bombardment of oxygen-18 enriched water through the nuclear reaction O(p,n)F. Aqueous solutions of F are rendered, from which the ion of interest can be isolated by ion-exchange chromatography. Gaseous [F]F2 is also available through the nuclear reaction Ne(d,a)F. The former facilitates nucleophilic fluorination reactions; the latter, electrophilic fluorination. Both reaction modes have important applications in PET imaging research. This article discusses recent strides in the field of F radiochemistry, categorized by the reaction motif. Gouverneur and co-workers recently disclosed the preparation of [F]Selectfluor bis(triflate) 1 as a means to broaden the scope and utility of electrophilic fluorination for F radiochemistry. Inspired by the mild, commercially available fluorinating agent Selectfluor, 1 was prepared through chloromethylation of diazabicyclo[2.2.2]octane, anion exchange, and subsequent fluorination using high-specific activity [F]F2 (Scheme 1). The resulting bis(triflate) was