A New and Improved Synthesis of the Precursor of the Hypoxia Marker [¹8F]-FMISO

Abstract

A new synthetic approach to the precursor of the hypoxia marker [ 18 F]-FMISO has been developed. Three different tosylation methods were studied for the preparation of the key intermediate. The overall yield is markedly higher than the yields reported for previous syntheses. The precursor was used to prepare [ 18 F]-FMISO and the results were comparable to those obtained when a commercial precursor was used.

2‐Nitroimidazole Based PET Tracers: Development of a General Synthetic Approach and Fluorination Methodology

“…The crude material was purified by flash column chromatography on silica gel (cyclohexane/EtOAc from 30 : 70 to 40 : 60) to obtain the desired product as a yellowish oil (209 mg, 1.06 mmol, 61 %). Analyses are in agreement with literature [22] . 1 H NMR (500 MHz, CDCl 3 ) δ 7.20 (d, J =0.9 Hz, 1H), 7.16 (dd, J =0.9 Hz, 1H), 4.73 (dt, J =13.8, 2.8 Hz, 1H), 4.46 (dddt, J =12.0, 8.9, 6.0, 2.8 Hz, 1H), 4.40–4.36 (m, 1H), 4.19–4.16 (m, 1H), 3.69 (ddd, J =8.9, 5.0, 2.8 Hz, 1H), 1.40 (s, 3H), 1.33 (s, 3H).…”

“…Inspired by Nieto et al. work, [22,25] we propose a reaction with solketal 2 . The Mitsunobu reaction performed under classical conditions (diisopropyl azodicarboxylate (DIAD), PPh 3 , THF, RT) indeed gave the desired product 3 with a satisfying yield of 61 % (Scheme 1).…”

“…Precursor synthesis FMISO (fluoromisonidazole) is the most prominent representative PET tracer from the 2-nitroimidazole family. The classical FMISO synthetic pathway is based upon nucleophilic addition of 2-nitroimidazole on 2,2-dimethyl-1,3-dioxolan-4-ylmethyl ptoluenesulfonate, [22] glycidol [23] or bis-tosylated glycerol. [24] However, those strategies suffer from major drawbacks such as poor yields or numerous synthetic steps.…”

“…In order to resolve these synthetic issues, we reasoned that thanks to the low pKa values of 2-nitroimidazoles (pKa = 8.7), a Mitsunobu reaction could be developed as a new synthetic approach for FMISO precursors. Inspired by Nieto et al work, [22,25] we propose a reaction with solketal 2. The Mitsunobu reaction performed under classical conditions (diisopropyl azodicarboxylate (DIAD), PPh 3 , THF, RT) indeed gave the desired product 3 with a satisfying yield of 61 % (Scheme 1).…”

“…Compounds 6 , [22] precursor of 26 [22] and bis‐tosylated FETNIM precursor [29] were prepared according to reported procedures.…”