Alcohol‐Enhanced Cu‐Mediated Radiofluorination

In this paper, we describe the use of Cu-mediated [ F]fluorodeboronation for the automated production of positron emission tomography radiotracers suitable for clinical use. Two recurrent issues with the method, low radiochemical conversion on automation and protoarene byproduct purification issues, have been successfully addressed. The new method was utilized to produce sterile injectable doses of [ F]-(±)-IPMICF17, a positron emission tomography radiotracer for tropomyosin receptor kinase B/C, using an automated synthesis module. The product was isolated in 1.9 ± 0.1% isolated radiochemical yield, excellent radiochemical purity (>99%), and high specific activity (5294 ± 1227 Ci/mmol). Quality control testing confirmed that doses were suitable for clinical use.

Section: Introductionmentioning

confidence: 99%

Automated synthesis of PET radiotracers by copper‐mediated ¹⁸F‐fluorination of organoborons: Importance of the order of addition and competing protodeborylation

Mossine

Brooks

Bernard‐Gauthier

et al. 2018

“…The diaryl iodonium salt gave the radiochemically‐pure product in 10% RCY and 75 GBq/μmol (2.0 Ci/μmol) . This tracer was also prepared by copper‐mediated radiofluorination with boronic ester as the precursor in 85% radiochemical conversion (RCC), 12% RCY, and 80 GBq/μmol (2.2 Ci/μmol) . Electrophilic fluorination with [ 18 F]Selectfluor as a labeling reagent was also performed to prepare [ 18 F]FDPA.…”

Section: Resultsmentioning

confidence: 99%

A concisely automated synthesis of TSPO radiotracer [¹⁸F]FDPA based on spirocyclic iodonium ylide method and validation for human use

Wang

Yao

Tang³

et al. 2020

Fluorine‐18 labeled N,N‐diethyl‐2‐(2‐(4‐(2‐fluoroethoxy)phenyl)‐5,7‐dimethylpyrazolo[1,5‐a]pyrimidin‐3‐yl)acetamide ([18F]FDPA) is a potent and selective radiotracer for positron‐emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO). Our previous in vitro and in vivo evaluations have proven that this tracer is promising for further human translation. Our study addresses the need to streamline the automatic synthesis of this radiotracer to make it more accessible for widespread clinical evaluation and application. Here, we successfully demonstrate a one‐step radiolabeling of [18F]FDPA based on a novel spirocyclic iodonium ylide (SCIDY) precursor using tetra‐n‐butyl ammonium methanesulfonate (TBAOMs), which has demonstrated the highest radiochemical yields and molar activity from readily available [18F]fluoride ion. The nucleophilic radiofluorination was completed on a GE TRACERlab FX2 N synthesis module, and the formulated [18F]FDPA was obtained in nondecay corrected (n.d.c) radiochemical yields of 15.6 ± 4.2%, with molar activities of 529.2 ± 22.5 GBq/μmol (14.3 ± 0.6 Ci/μmol) at the end of synthesis (60 minutes, n = 3) and validated for human use. This methodology facilitates efficient synthesis of [18F]FDPA in a commercially available synthesis module, which would be broadly applicable for routine production and widespread clinical PET imaging studies.

“…In previous reports, the copper‐mediated 18 F‐fluorination of amines required an acid‐catalyzed Boc‐deprotection in concentrated HCl or HI at 130°C as the second step, which would not be suitable for many even mildly acid‐sensitive compounds. We aimed to apply a concomitant thermal cleavage of the four Boc protecting groups to avoid acid‐catalyzed decarboxylation.…”

Section: Resultsmentioning

confidence: 99%

“…For the isolation of 18 F‐fluoride from the target [ 18 O]H 2 O, we applied the “minimalistic approach” originally reported by Zischler et al, which proved to be the most effective technique for the copper‐mediated synthesis of other 18 F‐labeled tracers in our hands . Briefly, [ 18 F]F − /H 2 O was passed through a Sep‐Pak Light QMA cartridge (46 mg, Waters) followed by anhydrous methanol (3 mL) to remove traces of water.…”

Section: Methodsmentioning

confidence: 99%

Efficient radiosynthesis and preclinical evaluation of [¹⁸F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

Singleton

Bdair

Bailey

et al. 2020

Herein we report an efficient radiolabeling of a 18F‐fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF‐1R). [18F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper‐mediated 18F‐fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [18F]FOMPyD showed moderate brain permeability in wild‐type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40–90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self‐blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF‐1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [18F]FOMPyD as a PET tracer for brain imaging, the concomitant one‐pot copper‐mediated 18F‐fluorination/Boc‐deprotection is a practical technique for the automated radiosynthesis of acid‐sensitive PET tracers.