Tetrahedron Letters
Nucleophilic 18F-fluorination of phosphorofluoridates and
phosphonofluoridic acids via imidazole-activated precursors
⇑
Zhaobiao Mou, Xueyuan Chen, Chao Wang, Tao Wang, Hongzhang Yang, Zijing Li
Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen
University, Xiamen 361102, China
a r t i c l e i n f o
a b s t r a c t
18F-Labeled organofluorophosphates are important radiosynthons that have only been previously acces-
sible via 18/19F-isotope-exchange with limited molar activities. Herein, a novel 18F-fluorination method-
ology has been developed to prepare 18F-labeled phosphorofluoridates and phosphonofluoridic acids
via the [18F]Fꢀ nucleophilic substitution of imidazole-activated precursors. The efficient one-step 18F-flu-
orination affords stable products in the presence of Zn(Ⅱ) with high radiochemical yields and high molar
activities. This 18F-fluorination method could be used to prepare various phosphorofluoridate and phos-
phonofluoridic acid analogs for use as 18F-radiosynthons and potential positron emission tomography
tracers.
Article history:
Received 19 December 2020
Revised 1 February 2021
Accepted 8 February 2021
Available online 16 February 2021
Keywords:
18F-Fluorination
Phosphorofluoridate
Phosphonofluoridic acid
Imidazole
Ó 2021 Elsevier Ltd. All rights reserved.
Nucleophilic substitution
Introduction
phosphorus moieties may involve individual synthesis of the pre-
cursors, multistep radiosynthesis [8], and potential change of
Phosphate and phosphonic acid groups are privileged scaffolds
that are widespread in biologically and medicinally active com-
pounds [1]. Additionally, radiolabeled phosphates and phosphonic
acids are irreplaceable as radiosynthons and radiotracers for the
investigation of phosphate-related physiological processes and dis-
eases [2]. In prior studies, only 32P-labeled phosphates were avail-
able to monitor their physiological pathways in vitro [3], which
could not provide real-time dynamic images in vivo due to the
nuclide property of 32P (100% b– decay). Instead, 18F (97% b+ decay,
635 keV, t1/2 ꢁ 109.8 min), the most widely used positron emitting
isotope, allows wide bioisosteric replacement and in vivo imaging
with positron emission tomography (PET) [4]. However, 18F-
labeled organofluorophosphates were only previously accessible
via 18/19F-isotope-exchange with limited molar activities (Am, the
measured radioactivity per mole of compound, measured in
bioactivity of the substrate [9]. Therefore, the ideal fluorination
sites are the terminal positions of the phosphate and phosphonic
acid groups. Imidazole-activated phosphates prepared via a one-
step coupling reaction from phosphates [10] can be fluorinated
using aqueous fluoride [11]. This process can be accelerated by
the presence of Lewis acids [12], making these promising candi-
dates for precursors. It was hypothesized that the same fluorina-
tion and coupling reaction may also be applicable to phosphonic
acids.
Herein, a method for the 18F-fluorination of phosphorofluori-
dates and phosphonofluoridic acids via imidazole-activated pre-
cursors is described. Zn2+ species were determined as the best
Lewis acid catalysts among the tested metal cations (e.g. Mg2+
and Mn2+) to facilitate the elimination of imidazole via activation
of the P-N bond [13]. In addition, the in vitro and in vivo stabilities
of the 18F-labeled phosphorofluoridates and phosphonofluoridic
acids were evaluated for potential applications as radiosynthons
and PET tracers.
Bq/mol or GBq/lmol) [5,6].
Due to analogous van der Waals radius and valence electron
numbers between fluoro and hydroxyl groups, fluorination of the
phosphate or phosphonic acid moiety can produce a chemically
stable phosphorofluoridate or phosphonofluoridic acid derivative
which is isostructural and isoelectronic to the unmodified
substrate [7]. Additionally, nucleophilic fluorination on non-
Results and discussion
Five imidazole-activated precursors, sodium (1H-imidazol-1-yl)
phosphonates (1a–4a) and sodium benzyl (1H-imidazol-1-yl)phos-
phinate (5a), were synthesized in 35–82% yield from the corre-
sponding phosphates or phosphonic acid via the one-step
⇑
Corresponding author.
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.