A practical, automated synthesis of meta-[(18)F]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-[(123)I]iodobenzylguanidine ([(123)I]MIBG) is limited by the emissions of (123)I, which lead to poor image resolution and challenges in quantification of its accumulation in tumors. meta-[(18)F]Fluorobenzylguanidine ([(18)F]MFBG) is a promising alternative to [(123)I]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 [(18)F]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 [(18)F]MFBG produced by this route demonstrated the tracer's suitability for human use. [(18)F]MFBG was prepared in almost 3-fold higher yield than previously reported (31% corrected to end of bombardment, n = 9) in a synthesis time of 56 min 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 [(18)F]MFBG. Moreover, if ongoing clinical imaging trials of [(18)F]MFBG are successful, this methodology is suitable for rapid commercialization and can be easily adapted for use on most commercial automated radiosynthesis equipment.

Keywords: [18F]MFBG; diaryliodonium salts; fluorine-18; meta-[18F]Fluorobenzylguanidine; positron emission tomography.

Figure 1

Comparison of the radiosynthesis of meta-[¹⁸F]fluorobenzylguanidine ([¹⁸F]MFBG) by (a) Garg et al., (b) Zhang et al., and (c) the method reported herein.

Figure 2

Deprotection of the fluorinated intermediate at various temperatures over time. Performed in 800 μL 6 M HCl, reaction halted for sampling every 5 minutes; n = 1 for each temperature.

Figure 3

Analytical HPLC of [¹⁸F]MFBG. Agilent Zorbax SB-Aq column (4.6 × 150 mm, 5 μm); 10% acetonitrile and 35 mM phosphoric acid, 25 mM monobasic sodium phosphate, pH 2; flow rate of 1 mL/min, monitoring at 220 nm. Note: a 0.3 min difference is expected between UV and radioactivity retention times due to the distance between the two detectors connected in series.

Figure 5

Stepwise process for synthesis of [¹⁸F]MFBG.

Scheme 1

Synthesis of N,N′,N″,N‴-tetrakis-BOC protected diaryliodonium salt 5^{a a}Reagents and conditions: a) m-iodobenzylamine HCl, Et₃N, CHCl₃, r.t., 80%; b) BOC₂O, Cat. DMAP, THF, r.t., 95%; c) Selectfluor^®, TMSOAc, r.t.; d) potassium (4-Et₃N, CH₃CN, methoxyphenyl)trifluoroborate, TMSOTf, CH₃CN, two steps: 68%.

Scheme 2

Synthesis of diaryliodonium salt 10^{a a}Reagents and conditions: a) m-iodobenzyl bromide, DCM/H₂O, Cat. Bu₄NI, KOH, 94%; b) bis(pinacolato)diboron, Cat. PdCl₂(PhCN)₂, Cat. 1,1′-bis(diphenylphosphino)ferrocene (DPPF), KOAc, DMSO, 80 °C, overnight; c) aq. KHF₂, methanol, two steps: 61%; d) 4-methoxyphenyl-iodonium diacetate, TMSOTf, CH₃CN, 66%; e) Selectfluor^®, TMSOAc, CH₃CN; f) 4-methoxyphenyl-trifluoroborate, TMSOTf, CH₃CN, two steps: 60%.