A Practical, Automated Synthesis of meta-[¹⁸F]Fluorobenzylguanidine for Clinical Use

Abstract

Many neuroendocrine tumors, such as neuroblastoma (NB), arise from neural crest cells of the sympathetic nervous system. This nerve-like phenotype has been exploited for functional imaging using radioactive probes originally designed for neuronal and adrenal medullary applications. NB imaging with meta-[123I]iodobenzylguanidine ([123I]MIBG) is limited by the emissions of 123I, which lead to poor image resolution and challenges in quantification of its accumulation in tumors. Meta-[18F]Fluorobenzylguanidine ([18F]MFBG) is a promising alternative to [123I]MIBG that could change the standard of practice for imaging neuroendocrine tumors, but interest in this PET radiotracer has suffered due to its complex and inefficient radiosynthesis. Here we report a two-step, automated method for the routine production of [18F]MFBG by thermolysis of a diaryliodonium fluoride and subsequent acid deprotection. The synthesis was adapted for use on a commercially available synthesizer for routine production. Full characterization of [18F]MFBG produced by this route demonstrated the tracer’s suitability for human use. [18F]MFBG was prepared in almost three-fold higher yield than previously reported (31% corrected to end of bombardment, n = 9) in a synthesis time of 56 minutes with > 99.9% radiochemical purity. Other than pH adjustment and dilution of the final product, no reformulation was necessary after purification. This method permits the automated production of multidose batches of clinical grade [18F]MFBG. Moreover, if ongoing clinical imaging trials of [18F]MFBG are successful, this methodology is suitable for rapid commercialization and can be easily adapted for use on most commercial automated radiosynthesis equipment.

Hypervalent aryliodine compounds as precursors for radiofluorination

“…Typically, the cation is introduced as a carbonate or bicarbonate salt. This approach is readily automated for radiotracer production and has been performed in custom‐built or commercial radiosynthesis devices …”

“…Earlier syntheses of this radiotracer had required 3 steps from [ 18 F]fluoride ion that were overall inefficient . An efficient 2‐step synthesis of [ 18 F]MFBG has been developed from 4‐anisyl(aryl)iodonium triflate having a fully protected guanidinyl group, based on generation of the [ 18 F]fluoride salt followed by thermolysis and acid deprotection (Table , entry 12) . The synthesis has been fully automated on a commercial radiosynthesis instrument (Synthera, IBA).…”

“…This approach is readily automated for radiotracer production and has been performed in custom-built or commercial radiosynthesis devices. 38,40,55,[69][70][71] Other approaches have also been explored for performing and studying the radiofluorination of diaryliodonium salts. One approach is described as "minimalist" as it uses neither the base nor other additives that are introduced in the conventional batch approach ( Figure 10).…”

“…132 An efficient 2-step synthesis of [ 18 F]MFBG has been developed from 4-anisyl(aryl)iodonium triflate having a fully protected guanidinyl group, based on generation of the [ 18 F]fluoride salt followed by thermolysis and acid deprotection ( Table 3, entry 12). 71 The synthesis has been fully automated on a commercial radiosynthesis instrument (Synthera, IBA). This procedure gives [ 18 F]MFBG for clinical use in 56 minutes and in almost 3-fold higher yield (31%) than previous methods.…”

Efficient Pathway for the Preparation of Aryl(isoquinoline)iodonium(III) Salts and Synthesis of Radiofluorinated Isoquinolines

“…[1] Attributed to the increasing prevalence of fluorine-containing pharmaceuticals and obstacles to the access of low specific activity electrophilic [ 18 F]F 2 ,f ocused efforts have been made to design novel methods to radiolabel non-activated arenes using nucleophilic [ 18 F]fluoride ion. [5k,l] Diaryliodonium salts have also shown to be useful in the production of PET radiotracers,i ncluding [ 18 F]TFB, [5d] [ 18 F]flumazenil, [6] [ 18 F]mFBG, [7] [5e, 9] Despite the significant role of radiofluorination using iodonium methods in the PET tracer development, the preparation of these hypervalent iodine precursors [10] necessitates oxidation of iodoarene in acid media [11] or exchange with organometallic species, [12] for example stannylated/boronated compounds,w hich are prepared from "Miyaura borylation" type cross-coupling reactions with the corresponding aryl halides (Scheme 1a). [5] In particular,r adiofluorination based on iodonium ylide precursors has demonstrated aw ide range of compatibility in the labeling of well-functionalized molecules and radiopharmaceuticals,f or instance, [ 18 [5m] and [ 18 F]3-fluoro-5-(2-pyridinylethynyl)benzonitrile ([ 18 F]FPEB), [5j] as well as application of 18 F-azido arenes in bioconjugation reactions.…”