Current Radiopharmaceuticals - Volume 3, Issue 2, 2010

Nowadays it is becoming increasingly commonplace for a physician to prescribe an FDG-PET scan, especially in oncology. FDG, short for 2-[18F]fluoro-2-deoxy-D-glucose, is a radioactive derivative of D-glucose that accumulates in tissue according to their degree of D-glucose utilization and is therefore very suitable to detect tumours and evaluate their metabolic state. The radiosynthesis of FDG was achieved for the first time in 1978 but it has been only in the last decade that its routine use in nuclear medicine has really taken on. The reason for this relatively long incubation time is twofold. It takes a certain time for a radiopharmaceutical to prove itself and to convince the medical profession of its utility. In addition there were technical and logistic problems to be solved. How to produce FDG regularly in sufficient quantities at a sufficient number of sites? A key factor in all this is radiochemistry know-how, which has seen considerable progress with time. For example, in the beginning FDG was made in relatively low yield with electrophilic [18F]F2 when today's efficient nucleophilic method with [18F]F- was not available. Indeed, the advent of a reliable method that renders cyclotron-produced aqueous and chemically unreactive [18F]fluoride suitable for nucleophilic substitution reactions has revolutionized radiopharmaceutical development with fluorine- 18. It is therefore not a co-incidence that all eleven contributions to the present “focus on [18F]fluoride radiochemistry”, covered by two successive issues of the journal, deal almost exclusively with nucleophilic radiofluorination. The present first issue (volume 3, number 2) begins with a concise outline of the field by Banister et al., the ideas of which are then developed more in depth in the following contributions. Introduction of fluoride in an aromatic position is less straightforward than aliphatic fluorination, the latter treated by Roeda and Dolle, and its methodology is accordingly more differentiated. This is reviewed in separate contributions by Ermert and Coenen, dealing successively with direct labelling at an activated position and built-up syntheses via small radiofluorinated synthons. The second issue (volume 3, number 3) will open with the third contribution by Ermert and Coenen, this time on the labelling of electron-rich arenes, completing the initial expose of the state of the art. Then Kuhnast and Dolle will look at the more specific field of macromolecule labelling which is rapidly gaining importance. Especially within this field of macromolecules two developments have recently attracted attention, both directed towards prosthetic group construction. The first is the copper(I)-catalyzed Huisgen coupling between a terminal alkyne and an azide, either labelled with fluorine-18, to give a triazole. This reaction, also known under the name “click chemistry” will be reviewed by Ross, followed by an article by Mu et al. on radiochemistry based on fluorine-silicon and fluorine-boron bond formation involving structures of the type RSi[18F]F4 -,R'R2Si[18F]F and RB[18F]F3. Then Martarello et al. will describe the recently discovered enzyme that can (radio)fluorinate adenosine giving access to various sugar- and nucleoside-like structures by coupled enzyme reactions. Our compilation will conclude with two contributions on technological developments. Sachinidis et al. give their view on the basic principles of automation, so important for safe and reliable routine production of radiopharmaceuticals while Miller at al take us to the fascinating world of extremely small reaction volumes in microfluidic technology that is not unlikely to have a big future in PET chemistry. It is clear that fluorine-18 radiochemistry has reached a certain degree of maturity and continues to strive after perfection and innovation, hopefully leading to new and useful radiopharmaceuticals as successful as FDG.

Fluorine-18 is the most important radionuclide used in positron emission tomography (PET) today, largely due to its attractive physical and nuclear characteristics. Agents such as the clinical oncology tracer 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), the most widely used PET-radiopharmaceutical, are driving an increasing interest in the chemistry of radiopharmaceuticals utilizing fluorine-18. This review outlines the methods for production of fluorine-18, and the development of agents for performing radiofluorination reactions. With a few exceptions, radiofluorinations can be classified as either electrophilic or nucleophilic. The electrophilic reactions mainly use molecular [18F]fluorine of moderately low specific radioactivity, or reagents prepared from it, and include additions to alkenes, reactions with carbanions and especially fluorodehydrogenation and fluorodemetallation. The nucleophilic reactions usually involve no-carrier-added (high-specific- radioactivity) [18F]fluoride as its K[18F]F-K222 complex and include SN2-type substitutions in the aliphatic series and SNAr-type substitutions in the aromatic and heteroaromatic series. Key examples from each class of radiofluorination reaction will be described, highlighting the potential of this radioisotope in the design and preparation of fluorine-18- labeled probes for PET imaging.

In this review we are looking at some aspects of nucleophilic aliphatic radiofluorination, notably the labelled fluoride source, design aspects, the leaving group and the solvent. It should be clear that there is more to this branch of radiolabelling than one would suspect from the frequently used standard tosylate replacement with kryptofix/[18F]fluoride in acetonitrile or DMSO. Competitive elimination can be a serious problem that can affect both yield and purification. Deprotection of sensitive groups after radiolabelling and its possible side reactions can complicate purification. The right choice of leaving group and protecting groups may be crucial. Newer developments such as the use of tertiary alcohols or ionic liquids as solvents, long-chain polyfluorinated sulphonate leaving groups facilitating fluorous solid phase extraction, or immobilisation of the precursor on a solid phase support may help to solve these problems, for example the long-standing problems with [18F]FLT, whereas older concepts such as certain cyclic reactive entities for ring opening or even an abandoned reagent as [18F]DAST should not be forgotten.

This review summarizes the possibilities of nucleophilic 18F-fluorination of complex molecules in activated carbocyclic aromatic position.

This review summarizes the possibilities of built-up syntheses of no-carrier-added radiofluorinated aromatic tracers via [18F]fluorobenzene derivatives as intermediate compounds.