Current Organic Chemistry - Volume 17, Issue 19, 2013

This paper revisits some aspects of carbon-11 radiochemistry from the production of the primary labeling reagents and fast chemical transformations used to convert them into more useful building blocks such as [11C]methyl iodide and [11C]carbon monoxide. The application facet covers traditional methylation, carboxylation and other reactions in the preparation of PET tracers. Technical aspects and strategies in handling labeling syntheses are also included. Distinct attention is then given to methods for the 11C-labelling of carbamide and carbamate functional groups at the carbonyl position, considering the wide choice of protocols and starting materials that have become available for this purpose. Concluding sections provide an overview of contemporary practices for the purification of labeled compounds and preventing their radiolytic decomposition.

This review article summarizes the recent information regarding general aspects in the automated synthesis of 18F-labelled PET radiotracers that are prepared via nucleophilic fluorination pathway. The previous and on-going researches in development of different automation solutions are discussed and the current trends in large scale production of radiotracers are considered. The advantages and limitations of the fully automated systems available from different manufacturers are exemplified by routine automated production of several clinically relevant 18F-radiotracers using traditional automated synthesizers, kit-based (cassette-type) radiochemistry modules and modular systems.

Sharpless et al. presented, in 2001, a review in which they introduced the concept of “click chemistry”. In this review a “new way” of making chemicals, with a particular emphasis on drugs, is presented. Current drugs are often based on natural products that were first extracted from plants or other organisms and then with enormous effort were synthetically reproduced by chemists. Sharpless et al. propose to shift the focus away from the structure, which chemists focus on when they synthesize natural products, towards the function of molecules. Rather than making natural products with known biological activity and using these as templates for small modifications, it is proposed to make large libraries of compounds using (mainly) modular chemistry. After all, when looking for new and better drugs, it is the function that matters rather than the structure. This approach mimics nature in that it involves making a great variety of different compounds starting from a relatively small number of building blocks via a set amount of reactions. These sets of reactions have been termed “click reactions” in which simple molecules with specific functionalities can be “clicked” to each other to form a large variety of compounds with relative ease that can subsequently be tested as potential drug candidates. For these “click reactions” Sharpless also looks to nature for inspiration. Ideally, the reaction conditions should be simple, involving no or benign solvents and the reaction itself should be insensitive to oxygen and water. It was found that copper not only accelerates the reaction but also controls the regioselectivity since in the presence of copper, only the 1,4-isomer is formed. The reaction proceeds in water, with or without co-solvent at room temperature and is relatively fast. The reaction is 100% atom efficient which means that there are no side products so the work up is usually simple. It can take place in a wide pH range which makes is suitable for biological compounds that require a specific pH. Furthermore the azide and alkyne functionalities are bioorthogonal, so theoretically, other functional groups present in a biological environment will not touch them. Finally the triazole product is biologically stable.

[11C]methyl iodide was originally produced by using LiAlH4 to reduce [11C]CO2 to [11C]methanol, followed by reaction with liquid hydriodic acid. However, it is difficult to obtain the desired high specific radioactivity of the end-product 11C-methylated tracer because the lithium reagent solution is so easily contaminated by atmospheric [11C]CO2 The introduction of high temperature gas-phase methodologies greatly enhanced the specific activity of 11C-labeled PET tracers by eliminating the lithium reagent entirely. Details for three commercially available gas-phase synthesis modules are provided and discussed with respect to ease-of-operation and preventative maintenance concerns. Lastly, C-11 target performance is discussed with respect to the in-target release of carrier [11C]carbon, the remaining obstacle to ultra-high specific activity for 11C-labeled PET tracers.

For PET applications in oncological and neurological diagnostics, amino acids have been studied both clinically and pre-clinically during the last 35 years. Nowadays two applications of labelled amino acids for visualisation of tumours attract the main attention: [11C] or [18F]amino acids as substrates of specific membrane transport systems or in vivo measurement of protein synthesis rate. In this review we focussed on 11C-labelled amino acids, since synthetic approaches to [18F]amino acids have been extensively reviewed in the literature. Most of optically pure 11C-labelled amino acids (except [11C]methionine) have been prepared via low-yield non-reliable synthetic procedures. Low availability hampers their evaluation as biological probes. The first synthesis of racemic [11C]lactic acid as an [11C]amino acid precursor was published in 1941. It took more than thirty years to develop the first synthesis of a racemic [11C]amino acid, it was published in 1973. Early examples of asymmetric synthesis of [11C]amino acids led to relatively low enantiomeric excess, up to 82%. Amino acids synthons developed by groups led by Oppolzer, Seebach, Belokon and Horwell allowed highly stereospecific preparation of [11C]amino acids. Enzymatic and biotechnological approaches, catalytic [11C]alkylation of achiral glycine synthons or catalytic hydrogenation of [11C]precursors have not resulted in any practically useful syntheses yet. The importance for PET using new α-substituted amino acids is briefly discussed.

Organic chemistry with short-lived positron emitters has evolved into a complex chemical science. Special efforts are focused on the development of rapid, selective and functional group-tolerating reactions with the most prominent short-lived positron emitter fluorine-18 (18F, 1/2= 109.8 min). The use of catalysts such as palladium complexes represents a highly promising approach for rapid and efficient syntheses of a wide variety of 18F-labeled PET radiotracers. Palladium-mediated cross-coupling reactions such as STILLE reaction, SUZUKI reaction, SONOGASHIRA reaction and BUCHWALD N-arylation with various 4-[18F]fluoro-halobenzenes as versatile 18F labeling building blocks were shown to be particularly effective reactions. More recently, various palladium-mediated electrophilic and nucleophilic late stage radiofluorination reactions have further expanded the scope of palladium complexes in 18F chemistry. In conclusion, palladium-mediated cross-coupling reactions have significantly advanced and will continue to advance the field of organic PET chemistry with 18F.

The automation of quality control methods used for release of [18F]fluoride-labeled radiotracers is a logical next step for increasing reliability and decreasing exposure in day-to-day clinical manufacture. In this work we evaluate the suitability for automation in six key release tests: Radiochemical purity and identity, determination of pH, kryptofix and residual solvents, as well as filter membrane integrity test. Results obtained for [18F]FDG, as proof of concept, were comparable to certified standards and conventional quality control following both USP and EP guidelines. The automated methods can be performed in 20 minutes without the need of an operator, and exhibited an overall higher precision compared to conventional quality control. A perspective on the potential significance of this automated approach is presented.

Due to favourable in-vivo characteristics, the long half-life of 18F (110 min) allowing for remote-site delivery and its high specificity, O-(2’-[18F]fluoroethyl)-L-tyrosine ([18F]FET) has gained increased importance for molecular imaging of cerebral tumors. Consequently, the development of simple and efficient production strategies for FET could be an important step to further improve the cost-effective availability of FET in the clinical environment. An earlier developed labeling approach using a chiral NiII complex of an alkylated (S)-tyrosine Schiff base, Ni-(S)-BPB-(S)-Tyr-OCH2CH2OTs (II) as a synthesis precursor provided a good means of preparing FET in high enantiomeric purity of 94-97%, but in moderate RCY. The aim of this study was to improve the 18F-fluorination efficiency of (II) by varying fluorinations conditions: reaction media (non protic and protic solvents), PTC/base system and temperature. A very high 18F-fluoride incorporation rate into (II) was achieved in kryptofix-mediated fluorinations in DMSO, however this route did not allow FET in high and reproducible enantiomeric purity that is essential for application in PET human studies. The attempted 18F-fluorination of (II) in tert-alcohols resulted in poor (t-BuOH) or moderate (t-amyl alcohol) incorporation rates and associated with difficulties in the process automation. From our current results we may conclude that the earlier developed acetonitrile/K2.2.2 remains the most appropriate solvent/ catalyst combination for use in the 18F-fluorination reaction for the preparation of enantiomerically pure FET starting from (II).

Among the contingency of methodologies available for bioconjugation, the Click dipolar [3+2] cycloaddition pathway that results in the formation of triazole linkage were extensively investigated during the last few years in a wide variety of molecular architectures – that ranges between small molecules and polymers. Synthetic feasibility as well as the stability and application of triazole linkage were explored and successfully accomplished in live cells, in vitro, in vivo and tissues. The objective of this review is to present recent reports of this synthetic methodology, as applied to oligonucleotide chemistry. Advances in development of Click solid supports, newer alkyne and azide building blocks, covalent conjugations at either termini (3',5'), internal sites (base, sugar and backbone), solid and solution-phase labeling strategies, and applications to oligonucleotide detection are summarized in this review.

Among the broad range of transition metal-catalyzed reactions, the Heck reaction is an attractive methodology frequently being used for the synthesis of natural and biologically active products, since a palladium-catalyzed reaction of this kind can directly create complex molecules under mild conditions from readily available starting materials. This feature article provides the comprehensive summary of currently available applications of this reaction in the total synthesis