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

Abstract

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.

Fluorinated carbohydrates for18F-positron emission tomography (PET)

“…It is pertinent to note that uptake was determined by autoradiography rather than by the PET image due to poor resolution. 120 The uptake in the surrounding tissues, no significant difference was noted compared to the control mice: this is consistent with the previous discussion on the lactosebased tracer Et-2 0 -[ 18 F]-FDL (38). Interestingly, 1 0 -[ 18 F]-FEL (39) was shown to be selective for the peritumoral tissue and no tracer accumulation in the pancreas was observed in the control group mice.…”

“…36,37 The addition of Kryptofix s [2.2.2] (8) was found to enhance fluoride nucleophilicity and, by extension, 18 F incorporation. 38 Under optimised conditions, the fluorination of 1,3,4,6-tetra-O-acetyl-2-Otrifluoromethanesulfonyl-b-D-manno-pyranose (7), followed by global deprotection using HCl, enabled 2-[ 18 F]-FDG (1) to be generated with an uncorrected yield of 44 AE 4% (Scheme 2). 35 Acidic hydrolysis with HCl, classically requiring elevated temperatures and longer reaction times, can be achieved at room temperature under basic conditions.…”

“…8A). 117 A notable advance stemmed from the introduction of 1 0 -[ 18 F]-FEL (39), a tracer with potentially similar activity to Et-2 0 -[ 18 F]-FDL (38) but which could be accessed much more efficiently. 118,119 In tumour-bearing mice, 1 0 -[ 18 F]-FEL (39) showed a significant increase of uptake in the peritumoral tissue (1.29 AE 0.295% ID per g), in comparison with the wild type (0.090 AE 0.010% ID per g).…”

One-Pot Radiosynthesis of [18F]Anle138b—5-(3-Bromophenyl)-3-(6-[18F]fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazole—A Potential PET Radiotracer Targeting α-Synuclein Aggregates

“…The [ 18 F]fluoride ion complex with the PTC can then be dried to remove water and provide a reactive intermediate. In some instances, bulky counter-ions used for solubilisation of the [ 18 F]fluoride, such as R 4 N + (R = Et or n Bu), are introduced separately as salts (e.g., HCO 3 , tosylate, triflate); use of such phase-transfer catalysts can simplify trapping/elution procedures [ 27 ].…”

A closer look at the synthesis of 2-[18F]fluoroethyl tosylate to minimize the formation of volatile side-products

“…It is broadly discussed in the literature how harsh basic conditions might lead to degradation of precursors and reaction products leading to formation of side-products (Jacobson et al 2015;Kniess et al 2015;Carberry et al 2011;Krasikova and Orlovskaya 2022). In this regard, Fedorynski and coworkers (Fedorynski et al 1978) used a combination of sodium and/or potassium carbonates that alongside with crown ethers formed strong bases in organic solvents for generation and reactions of a variety of carbanions.…”