Perfusion Imaging in Clinical Practice: A Multimodality Approach to Tissue Perfusion Analysis

Abstract

327 Objectives Due to their electron-rich aromatic structure, nucleophilic fluorination of pyridines is challenging, especially at the meta position. Methods that generally work well for making ortho and para fluorinated pyridines do not work for meta substituted pyridines. Meta substitutions are possible through precursors such as iodonium salts and iodonium ylides, which are often difficult to prepare. In this project, we produce meta fluorinated 3-fluoro-4-aminopyridine (a brain radiotracer currently under investigation for multiple sclerosis) by direct nucleophilic fluorination of an off-the-shelf N-oxide precursor. Methods - Standard techniques in organic synthesis and radiochemistry - Solid phase extraction, radioHPLC and radioTLC - Automation of the synthesis using Synthera (IBA Radiopharmacy solutions) is currently ongoing Results [18F]3F4AP was produced in two steps by direct fluorination of 3-bromo-4-nitropyridine N-oxide followed by reduction using hydrogen gas catalyzed by 10% Pd/C. The fluorination reaction resulted in 25 ± 4% decay-corrected yield (n = 6) and the hydrogenation of the intermediate resulted in 55 ± 11% decay-corrected yield (n = 6). Fluorination was conducted at room temperature for 15 min. Total synthesis time including HPLC purification and quality control was 2 h and the overall radiochemical yield was 2.5% non-decay-corrected with most of the activity lost during the multiple purifications and transfers. Automation of this process should further increase the yield. Conclusions The use of pyridine N-oxides as substrates in fluorination reactions is unprecedented in the chemical literature. While the corresponding pyridine preferentially reacts at the ortho and para positions, the pyridine N-oxide preferentially reacts at the meta position. This is probably due to the strong electron-withdrawing effects of the N-oxide, which drastically changes the reactivity of the pyridine. The widespread availability of N-oxides and ease of reduction of the N-oxide group makes this reaction a promising new method for the production of meta fluorinated pyridines and other electron rich aromatics. $$graphic_9ADF8554-E16D-48C9-88C4-582F95C31044$$