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.

The aluminium-[18F]fluoride revolution: simple radiochemistry with a big impact for radiolabelled biomolecules

The aluminium-[18F]fluoride ([18F]AlF) radiolabelling method combines the favourable decay characteristics of fluorine-18 with the convenience and familiarity of metal-based radiochemistry and has been used to parallel gallium-68 radiopharmaceutical developments. As such, the [18F]AlF method is popular and widely implemented in the development of radiopharmaceuticals for the clinic. In this review, we capture the current status of [18F]AlF-based technology and reflect upon its impact on nuclear medicine, as well as offering our perspective on what the future holds for this unique radiolabelling method.

18F-Fluorination Using Tri-Tert-Butanol Ammonium Iodide as Phase-Transfer Catalyst: An Alternative Minimalist Approach

The 18F syntheses of tracers for positron emission tomography (PET) typically require several steps, including extraction of [18F]fluoride from H2[18O]O, elution, and drying, prior to nucleophilic substitution reaction, being a laborious and time-consuming process. The elution of [18F]fluoride is commonly achieved by phase transfer catalysts (PTC) in aqueous solution, which makes azeotropic drying indispensable. The ideal PTC is characterized by a slightly basic nature, its capacity to elute [18F]fluoride with anhydrous solvents, and its efficient complex formation with [18F]fluoride during subsequent labeling. Herein, we developed tri-(tert-butanol)-methylammonium iodide (TBMA-I), a quaternary ammonium salt serving as the PTC for 18F-fluorination reactions. The favorable elution efficiency of [18F]fluoride using TBMA-I was demonstrated with aprotic and protic solvents, maintaining high 18F-recoveries of 96–99%. 18F-labeling reactions using TBMA-I as PTC were studied with aliphatic 1,3-ditosylpropane and aryl pinacol boronate esters as precursors, providing 18F-labeled products in moderate-to-high radiochemical yields. TBMA-I revealed adequate properties for application to 18F-fluorination reactions and could be used for elution of [18F]fluoride with MeOH, omitting an additional base and azeotropic drying prior to 18F-labeling. We speculate that the tert-alcohol functionality of TBMA-I promotes intermolecular hydrogen bonding, which enhances the elution efficiency and stability of [18F]fluoride during nucleophilic 18F-fluorination.

Labelling via [Al18F]2+ Using Precomplexed Al-NODA Moieties

Over the past 20 years, 68Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with 68Ge/68Ga generators is limited as well as the number of patient doses per batch of 68Ga radiopharmaceutical. In the recent years, a new technique appeared, making use of the ease of aqueous labelling via chelators as with 68Ga but using 18F instead. This technique takes advantage of the strong coordinative bond between aluminium and fluoride, realized in the aqueous cation [Al18F]2+. Most applications to date make use of one-pot syntheses with free Al(III) ions in the system. In contrast, we investigated the labelling approach split into two steps: generating the Al-bearing precursor in pure form and using this Al compound as a precursor in the labelling step with aqueous [18F]fluoride. Hence, no free Al3+ ions are present in the labelling step. We investigated the impact of parameters: temperature, pH, addition of organic solvent, and reaction time using the model chelator NH2-MPAA-NODA. With optimized parameters we could stably achieve a 80% radiochemical yield exerting a 30-min reaction time at 100 °C. This technique has the potential to become an important approach in radiopharmaceutical syntheses.

Novel late-stage radiosynthesis of 5-[18F]-trifluoromethyl-1,2,4-oxadiazole (TFMO) containing molecules for PET imaging

Small molecules that contain the (TFMO) moiety were reported to specifically inhibit the class-IIa histone deacetylases (HDACs), an important target in cancer and the disorders of the central nervous system (CNS). However, radiolabeling methods to incorporate the [18F]fluoride into the TFMO moiety are lacking. Herein, we report a novel late-stage incorporation of [18F]fluoride into the TFMO moiety in a single radiochemical step. In this approach the bromodifluoromethyl-1,2,4-oxadiazole was converted into [18F]TFMO via no-carrier-added bromine-[18F]fluoride exchange in a single step, thus producing the PET tracers with acceptable radiochemical yield (3–5%), high radiochemical purity (> 98%) and moderate molar activity of 0.33–0.49 GBq/umol (8.9–13.4 mCi/umol). We validated the utility of the novel radiochemical design by the radiosynthesis of [18F]TMP195, which is a known TFMO containing potent inhibitor of class-IIa HDACs.

Scalable 18F Processing Conditions for Copper-Mediated Radiofluorination Chemistry Facilitate "Design of Experiments" (DoE) Optimization Studies and Afford an Improved Synthesis of [18F]Olaparib.

A convenient, scalable, and azeotropic drying free method for processing [18F]fluoride as base free<br>[18F]TBAF is reported and applied to copper-mediated radiofluorination (CMRF) radiosyntheses. A central<br>feature of this method is that a single production of [18F]TBAF can be divided into small aliquots that can be<br>used to perform multiple small-scale reactions in DoE optimization studies. The results of these studies can<br>then be reliably translated to full batch tracer productions using automated synthesizers. This processing<br>technique was successfully applied to the manual DoE optimization, DoE study validation, and subsequent<br>full-batch automation of the PARP-1 tracer [18F]olaparib. After DoE optimization, we were able to produce<br>[18F]olaparib in high radiochemical yields via both manual (%RCY (CMRF step only) = 78 ± 6 %, n = 4) and<br>automated (up to 80% radiochemical yield (%RCY); 41% activity yield (%AY)) radiosynthesis procedures.<br>This work further demonstrates the power of the DoE approach for improving the radiochemical yields and<br>radiosynthesis performance of clinically relevant tracer productions