Nucleophilic Synthesis of 6-l-[18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer?

Positron emission tomography employing 6-l-[18F]fluoro-3,4-dihydroxyphenylalanine (6-l-[18F]FDOPA) is currently a highly relevant clinical tool for detection of gliomas, neuroendocrine tumors and evaluation of Parkinson’s disease progression. Yet, the deficiencies of electrophilic synthesis of 6-l-[18F]FDOPA hold back its wider use. To fulfill growing clinical demands for this radiotracer, novel synthetic strategies via direct nucleophilic 18F-radiloabeling starting from multi-Curie amounts of [18F]fluoride, have been recently introduced. In particular, Cu-mediated radiofluorination of arylpinacol boronates and arylstannanes show significant promise for introduction into clinical practice. In this short review these current developments will be discussed with a focus on their applicability to automation

Phase Transfer Catalysts and Role of Reaction Environment in Nucleophilc Radiofluorinations in Automated Synthesizers

Incorporation of [18F]fluorine into PET radiotracer structure has traditionally been accomplished via nucleophilic pathways. The [18F]fluoride is generated in an aqueous solution via proton irradiation of oxygen-18 enriched water and must to be introduced into water-free organic solutions in order to generate reactive species. Thus nucleophilic 18F-fluorination traditionally included steps for [18F]fluoride concentration on the anion exchange resin, followed by removal of residual water via azeotropic distillation with MeCN, a time-consuming process associated with radioactivity losses and difficult automation. To circumvent this, several adsorption/elution protocols were developed based on the minimization of water content in traditional kryptofix-based [18F]fluoride eluents. The use of pre-dried KOH/kryptofix solutions, tertiary alcohols, and strong organic bases was found to be effective. Advances in transition metal-mediated SNAr approaches for radiolabeling of non-activated aromatic substrates have prompted development of alternative techniques for reactive [18F]fluoride species generation, such as organic solutions of non-basic alkyl ammonium and pyridinium sulfonates, etc. For radiofluorinations of iodonium salts precursors, a “minimalist” approach was introduced, avoiding the majority of pitfalls common to more complex methods. These innovations allowed the development of new time-efficient and convenient work-up procedures that are easily implementable in modern automated synthesizers. They will be the subject of this review

Automated Optimized Synthesis of [18F]FLT Using Non-Basic Phase-Transfer Catalyst with Reduced Precursor Amount

3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a positron emission tomography (PET) tracer useful for tumor proliferation assessment for a number of cancers, particularly in the cases of brain, lung, and breast tumors. At present [18F], FLT is commonly prepared by means of the nucleophilic radiofluorination of 3-N-Boc-5′-O-DMT-3′-O-nosyl thymidine precursor in the presence of a phase-transfer catalyst, followed by an acidic hydrolysis. To achieve high radiochemical yield, relatively large amounts of precursor (20–40 mg) are commonly used, leading to difficulties during purification steps, especially if a solid-phase extraction (SPE) approach is attempted. The present study describes an efficient method for [18F]FLT synthesis, employing tetrabutyl ammonium tosylate as a non-basic phase-transfer catalyst, with a greatly reduced amount of precursor employed. With a reduction of the precursor amount contributing to lower amounts of synthesis by-products in the reaction mixture, an SPE purification procedure using only two commercially available cartridges—OASIS HLB 6cc and Sep-Pak Alumina N Plus Light—has been developed for use on the GE TRACERlab FX N Pro synthesis module. [18F]FLT was obtained in radiochemical yield of 16 ± 2% (decay-corrected) and radiochemical purity >99% with synthesis time not exceeding 55 min. The product was formulated in 16 mL of normal saline with 5% ethanol (v/v). The amounts of chemical impurities and residual solvents were within the limits established by European Pharmacopoeia. The procedure described compares favorably with previously reported methods due to simplified automation, cheaper and more accessible consumables, and a significant reduction in the consumption of an expensive precursor

Automation of Copper-Mediated ¹⁸F-Fluorination of Aryl Pinacol Boronates Using 4-Dimethylaminopyridinium Triflate

Currently, the copper-mediated radiofluorination of aryl pinacol boronates (arylBPin) using the commercially available, air-stable Cu(OTf)2Py4 catalyst is one of the most efficient synthesis approaches, greatly facilitating access to a range of radiotracers, including drug-like molecules with nonactivated aryl scaffolds. Further adjustment of this methodology, in particular, the [18F]fluoride recovery step for the routine preparation of radiotracers, has been the focus of recent research. In our recent study, an organic solution of 4-dimethylaminopyridinium trifluoromethanesulfonate (DMAPOTf) was found to be an efficient PTC for eluting radionuclides retained on the weak anion exchange cartridge, Oasis WAX 1cc, employing the inverse sorption–elution protocol. Notably, the following Cu-mediated radiofluorination of arylBPin precursors in the presence of the Cu(OTf)2(Py)4 catalyst can be performed with high efficiency in the same solvent, bypassing not only the conventional azeotropic drying procedure but any solvent replacement. In the current study, we aimed to translate this methodology, originally developed for remote-controlled operation with manual interventions, into the automated synthesis module on the TRACERlab automation platform. The adjustment of the reagent amounts and solvents allowed for high efficiency in the radiofluorination of a series of model arylBPin substrates on the TRACERlab FXFE Pro synthesis module, which was adapted for nucleophilic radiofluorinations. The practical applicability of the developed radiofluorination approach with DMAPOTf elution was demonstrated in the automated synthesis of 6-L-[18F]FDOPA. The radiotracer was obtained with an activity yield (AY; isolated, not decay-corrected) of 5.2 ± 0.5% (n = 3), with a synthesis time of ca. 70 min on the TRACERlab FX N Pro automation platform. The obtained AY was comparable with one reported by others (6 ± 1%) using the same boronate precursor, while a slightly higher AY of 6-L-[18F]FDOPA (14.5 ± 0.5%) was achieved in our previous work using commercially available Bu4NOTf as the PTC

Production of 6-L-[18F]Fluoro-m-tyrosine in an Automated Synthesis Module for 11C-Labeling

6-L-[18F]Fluoro-m-tyrosine (6-L-[18F]FMT) represents a valuable alternative to 6-L-[18F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson’s disease. However, clinicalapplications of 6-L-[18F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-L-[18F]FMT using alcoholenhancedCu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic Bu4ONTf using a volatile iPrOH/MeCN mixture as reaction solvent. A simple and fast radiolabeling procedure afforded the tracer in 20.0 3.0% activity yield within 70 min. The developed method was directly implemented onto a modified TracerLab FX C Pro platform originally designed for 11C-labeling. This method enables an uncomplicated switch between 11C- and 18F-labeling. The simplicity of the developed procedure enables its easy adaptation to other commercially available remote-controlled synthesis units and paves the way for a widespread application of 6-L-[18F]FMT in the clinic

Rapid 18 F-labeling via Pd-catalyzed S -arylation in aqueous medium

We report radiolabeling of thiol-containing substrates via Pd-catalyzed S-arylation with 2-[18F]fluoro-5-iodopyridine, which is readily accessible using the “minimalist” radiofluorination method. The practicality of the procedure was confirmed by preparation of a novel PSMA-specific PET-tracer as well as labeling of glutathione, Aβ oligomer-binding RD2 peptide, bovine serum albumin and PSMA I&S

Alcohol-Supported Cu-Mediated F-18-Fluorination of Iodonium Salts under Minimalist Conditions

In the era of personalized precision medicine, positron emission tomography (PET) and related hybrid methods like PET/CT and PET/MRI gain recognition as indispensable tools of clinical diagnostics. A broader implementation of these imaging modalities in clinical routine is closely dependent on the increased availability of established and emerging PET-tracers, which in turn could be accessible by the development of simple, reliable, and efficient radiolabeling procedures. A further requirement is a cGMP production of imaging probes in automated synthesis modules. Herein, a novel protocol for the efficient preparation of F-18-labeled aromatics via Cu-mediated radiofluorination of (aryl)(mesityl) iodonium salts without the need of evaporation steps is described. Labeled aromatics were prepared in high radiochemical yields simply by heating of iodonium [F-18]fluorides with the Cu-mediator in methanolic DMF. The iodonium [F-18]fluorides were prepared by direct elution of F-18(-) from an anion exchange resin with solutions of the corresponding precursors in MeOH/DMF. The practicality of the novel method was confirmed by the racemization-free production of radiolabeled fluorophenylalanines, including hitherto unknown 3-[F-18]FPhe, in 22-69% isolated radiochemical yields as well as its direct implementation into a remote-controlled synthesis unit