An efficient radiosynthesis of [18F]fluoromisonidazole

doi:10.1016/0969-8043(93)90110-V

Applied Radiation and Isotopes

Volume 44, Issue 8, August 1993, Pages 1085-1091

https://doi.org/10.1016/0969-8043(93)90110-V Get rights and content

Abstract

An efficient preparation of the hypoxic cell tracer [¹⁸F]3-fluoro-1-(2′-nitro-1′-imidazolyl)-2-propanol ([¹⁸F]fluoromisonidazole) is reported. This radiopharmaceutical is of interest to probe hypoxic tissue in infarcts and tumors. One-step radiolabeling and rapid protection group removal provided 55–80% yield in 50 min. The process is similar to common fluorine labeling procedures, simplifying the procedure for most laboratories, and offers an improvement over more difficult previous methods. The labeling precursor was prepared in five steps from readily available materials in a straightforward reaction scheme.

References (24)

T. Chaly et al.
A large scale manual production of [¹⁸F]FDG using a synthetic unit made of sterile disposable components and operated by a master slave manipulator
Appl. Radiat. Isot.
(1990)
A.J. Franko
Misonidazole and other hypoxia markers: metabolism and applications
Int. J. Rad. Oncol. Biol. Phys.
(1986)
P.A. Jerabek et al.
Synthesis and biodistribution of [¹⁸F]fluoronitroimidazole: potential in vivo markers of hypoxic tissue
Appl. Radiat. Isot.
(1986)
J.S. Rasey et al.
Radiolabeled fluoromisonidazole as an imaging agent for tumor hypoxia
Int. J. Radiat. Oncol. Biol. Phys.
(1989)
T.J. Tewson et al.
Routine production of reactive fluorine-18 fluoride salts from an oxygen-18 water target
Nucl. Med. Biol.
(1988)
K.C. Agrawal et al.
Potential radiosensitizing agents. Dinitroimidazoles
J. Med. Chem.
(1979)
N. Baggett et al.
Aspects of stereochemistry. Part IV. Configuration and some reactions of the 1,3-O-benzylideneglycerols
J. Chem. Soc.
(1960)
A.G. Beaman et al.
Studies in the nitroimidazole series
Antimicrob Agents Chemother
(1966)
M.S. Berridge et al.
Cyclic sulfates: useful substrates for selective nucleophilic substitution
J. Org. Chem.
(1990)
Y. Gao et al.
Vicinal diol cyclic sulfates: like epoxides only more reactive
J. Am. Chem. Soc.
(1988)

J.R. Grierson et al.

A radiosynthesis of fluorine-18-fluoromisonidazole

J. Nucl. Med.

(1989)

Z. Grunbaum et al.

Synthesis and characterization of congeners of misonidazole for imaging hypoxia

J. Nucl. Med.

(1987)

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Investigating tumor-host response dynamics in preclinical immunotherapy experiments using a stepwise mathematical modeling strategy
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Immunotherapies such as checkpoint blockade to PD1 and CTLA4 can have varied effects on individual tumors. To quantify the successes and failures of these therapeutics, we developed a stepwise mathematical modeling strategy and applied it to mouse models of colorectal and breast cancer that displayed a range of therapeutic responses. Using longitudinal tumor volume data, an exponential growth model was utilized to designate response groups for each tumor type. The exponential growth model was then extended to describe the dynamics of the quality of vasculature in the tumors via [¹⁸F] fluoromisonidazole (FMISO)-positron emission tomography (PET) data estimating tumor hypoxia over time. By calibrating the mathematical system to the PET data, several biological drivers of the observed deterioration of the vasculature were quantified. The mathematical model was then further expanded to explicitly include both the immune response and drug dosing, so that model simulations are able to systematically investigate biological hypotheses about immunotherapy failure and to generate experimentally testable predictions of immune response. The modeling results suggest elevated immune response fractions (> 30 %) in tumors unresponsive to immunotherapy is due to a functional immune response that wanes over time. This experimental-mathematical approach provides a means to evaluate dynamics of the system that could not have been explored using the data alone, including tumor aggressiveness, immune exhaustion, and immune cell functionality.
Azeotropic drying-free aliphatic radiofluorination to produce PET radiotracers in a mixed organic solvent system
2018, Tetrahedron Letters
Efficient aliphatic radiofluorination in a mixed organic solvent system was investigated. This method obviates the time-consuming [¹⁸F]fluoride drying step routinely required in the preparation of most fluorine-18 positron emission tomography (PET) radiotracers. The [¹⁸F]fluoride ions eluted from a QMA (quaternary ammonium anion exchange) cartridge with phase transfer agents were directly mixed in various organic solvents for subsequent radiofluorination. Herein, we report the azeotropic drying-free radiofluorination of aliphatic substrates and demonstrate the viability of hydrated [¹⁸F]fluoride ions in a mixed organic solvent system for obtaining useful radiochemical yields (RCYs). This practical and simple method has demonstrated general applicability to the production of established PET tracers as well as to the rapid assessment and chemical optimization of early-stage potential radiotracers.
Minimization of the amount of Kryptofix 222 - KHCO<inf>3</inf> for applications to microscale 18F-radiolabeling
2017, Applied Radiation and Isotopes
Conversion of aqueous [¹⁸F]fluoride to reactive [¹⁸F]fluoride is an important first step in the radiosynthesis of ¹⁸F-labeled compounds by nucleophilic substitution. A versatile method for the rapid preparation of reactive [¹⁸F]fluoride by the combined use of an Oasis MAX cartridge and a methanolic solution of the Kryptofix 222-KHCO₃ complex (K.222/KHCO₃) was developed. The latter amount was optimized with the aim to keep it as low as possible while achieving recovery yields of [¹⁸F]fluoride comparable to those attained with the commonly used QMA cartridge. Thus, a 97% recovery yield was obtained with just 2 µmol of K.222/KHCO₃ methanolic solution (10 mM, 200 µL) within 7 min. This result allowed in turn to optimize the microscale radiosynthesis of [¹⁸F]FDG. Moreover, the method was successfully applied to the 100 µL-scale ¹⁸F-substitution reactions of several precursors.
Synthesis of [18F]FMISO in a flow-through microfluidic reactor: Development and clinical application
2015, Nuclear Medicine and Biology
Citation Excerpt :
Earlier radiosyntheses of [18F]FMISO utilized multi-step procedures that gave low radiochemical yield [5–7]. Lim and Berridge then developed a one-pot, two-step procedure using 1-(2’-nitro-1’-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol (NITTP) as the precursor for [18F]fluorination followed by acidic hydrolysis to remove the protecting group, which resulted in greatly improved radiochemical yield and operational ease (Fig. 1) [8]. This is now the most widely used method for the production of [18F]FMISO.
The PET radiotracer [¹⁸F]FMISO has been used in the clinic to image hypoxia in tumors. The aim of the present study was to optimize the radiochemical parameters for the preparation of [¹⁸F]FMISO using a microfluidic reaction system. The main parameters evaluated were (1) precursor concentration, (2) reaction temperature, and (3) flow rate through the microfluidic reactor. Optimized conditions were then applied to the batch production of [¹⁸F]FMISO for clinical research use.
For the determination of optimal reaction conditions within a flow-through microreactor synthesizer, 5–400 μL the precursor and dried [¹⁸F]fluoride solutions in acetonitrile were simultaneously pushed through the temperature-controlled reactor (60–180 °C) with defined flow rates (20–120 μL/min). Radiochemical incorporation yields to form the intermediate species were determined using radio-TLC. Hydrolysis to remove the protecting group was performed following standard vial chemistry to afford [¹⁸F]FMISO.
Optimum reaction parameters for the microfluidic set-up were determined as follows: 4 mg/mL of precursor, 170 °C, and 100 μL/min pump rate per reactant (200 μL/min reaction overall flow rate) to prepare the radiolabeled intermediate. The optimum hydrolysis condition was determined to be 2 N HCl for 5 min at 100 °C. Large-scale batch production using the optimized conditions gave the final, ready for human injection [¹⁸F]FMISO product in 28.4 ± 3.0% radiochemical yield, specific activity of 119 ± 26 GBq/μmol, and > 99% radiochemical and chemical purity at the end of synthesis (n = 4).
By using the NanoTek microfluidic synthesis system, [¹⁸F]FMISO was successfully prepared with good specific activity and high radiochemical purity for human use. The product generated from large-scale batch production using flow chemistry is currently being used in clinical research.
Synthesis of [18F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist’s perspective
2023, EJNMMI Radiopharmacy and Chemistry
2-Nitroimidazole Based PET Tracers: Development of a General Synthetic Approach and Fluorination Methodology
2023, European Journal of Organic Chemistry

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Applied Radiation and Isotopes

Abstract

References (24)

A large scale manual production of [¹⁸F]FDG using a synthetic unit made of sterile disposable components and operated by a master slave manipulator

Appl. Radiat. Isot.

Misonidazole and other hypoxia markers: metabolism and applications

Int. J. Rad. Oncol. Biol. Phys.

Synthesis and biodistribution of [¹⁸F]fluoronitroimidazole: potential in vivo markers of hypoxic tissue

Appl. Radiat. Isot.

Radiolabeled fluoromisonidazole as an imaging agent for tumor hypoxia

Int. J. Radiat. Oncol. Biol. Phys.

Routine production of reactive fluorine-18 fluoride salts from an oxygen-18 water target

Nucl. Med. Biol.

Potential radiosensitizing agents. Dinitroimidazoles

J. Med. Chem.

Aspects of stereochemistry. Part IV. Configuration and some reactions of the 1,3-O-benzylideneglycerols

J. Chem. Soc.

Studies in the nitroimidazole series

Antimicrob Agents Chemother

Cyclic sulfates: useful substrates for selective nucleophilic substitution

J. Org. Chem.

Vicinal diol cyclic sulfates: like epoxides only more reactive

J. Am. Chem. Soc.

A radiosynthesis of fluorine-18-fluoromisonidazole

J. Nucl. Med.

Synthesis and characterization of congeners of misonidazole for imaging hypoxia

J. Nucl. Med.

Cited by (100)

Investigating tumor-host response dynamics in preclinical immunotherapy experiments using a stepwise mathematical modeling strategy

Azeotropic drying-free aliphatic radiofluorination to produce PET radiotracers in a mixed organic solvent system

Minimization of the amount of Kryptofix 222 - KHCO<inf>3</inf> for applications to microscale <sup>18</sup>F-radiolabeling

Synthesis of [<sup>18</sup>F]FMISO in a flow-through microfluidic reactor: Development and clinical application

Synthesis of [<sup>18</sup>F]FMISO, a hypoxia-specific imaging probe for PET, an overview from a radiochemist’s perspective

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