Synthesis of meta-substituted [¹⁸F]3-fluoro-4-aminopyridine via direct radiofluorination of pyridine N-oxides

Abstract

Due to their electron-rich aromatic structure, nucleophilic (radio)fluorination of pyridines is challenging, especially at the meta position. In this paper, we describe the first example of direct fluorination of a pyridine N-oxide to produce a metafluorinated pyridine. Specifically, fluorination of 3-bromo-4-nitropyridine N-oxide produced in several minutes 3-fluoro-4-nitropyridine N-oxide in moderate yield at room temperature. This intermediate compound was later converted to 3-fluoro-4-aminopyridine easily by catalytic hydrogenation. Furthermore, this approach was succesfully applied for labeling with fluorine-18. The use of pyridine N-oxides for the preparation of fluoropyridines is unprecedented in the chemical literature and has the potential to offer a new way for the synthesis of these important structures in pharmaceuticals and radiopharmaceuticals.

Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques

“…This is due to the increased level of expression of K v 1 channels in those areas as well as the increased accessibility of the drug to the channels given the lack of myelin 19,20,29,30 . It has also been reported that 3F4AP can be labeled with fluorine-18 [31][32][33] and that radiofluorinated [ 18 F]3F4AP can be used to detect chemically-induced demyelinated lesions in rat brains using PET 27 . The high sensitivity of this tracer towards demyelination makes it a promising candidate for imaging many neurological diseases where there is demyelination including MS, TBI, SCI, stroke, AD, and others 30 .…”

An efficient new method for the synthesis of 3‐[18F]fluoro‐4‐aminopyridine via Yamada‐Curtius rearrangement

“…The overall radiochemical yield was comparable with the manual synthesis with a specific activity of 37 to 148 GBq/μmol (n = 12). As reported in the recent literature, this tracer was synthesized with 2.5% (noncorrected) of radiochemical yield and with a specific activity of 0.37 to 3.7 GBq/μmol.…”

“…They prepared the fluorine‐18 analog of 3‐fluoro‐4‐aminopyridine (Scheme ) by halogen (Br or F) exchange followed by hydrogenation. Nevertheless, this method suffered from low overall radiochemical yield or low specific activity . Therefore, new methods to prepare fluorine‐18 labeled 3‐fluoro‐4‐aminopyridine in better radiochemical yield and higher specific activity are warranted.…”

“…To our knowledge, the Yamada‐Curtius rearrangement has never been used in the synthesis of PET radiopharmaceuticals. This method may be a superior alternative to other literature methods for preparing fluorine‐18‐labeled aminoheterocycles …”

Structure-activity relationship studies of three novel 4-aminopyridine K+ channel blockers

“…Mechanistically, 4AP blocks the exposed K + channels and therefore enhances conduction 16,17,19,20,[29][30][31][32] . Recently, it has been shown that the fluorinated derivative 3-fluoro-4-aminopyridine (3F4AP) also binds to these channels 33 and, once labeled with 18 F, can serve to detect areas of demyelination using positron emission tomography (PET) [33][34][35][36][37] . Given the potential of these molecules as therapeutic and imaging agents, we set out to investigate three new 4AP derivatives and their structure-activity relationships.…”