This chapter focuses on the current nucleophilic radiochemistry with [18F]fluoride illustrated with recent developments. Radiofluorination with [18F]fluoride implies nucleophilic substitution reactions. The chapter reviews recent progress in the conversion of [18F]fluoride into electrophilic fluorine-18 with a specific radioactivity (SRA) intermediate between that of [18F]fluoride and the habitual low value of [18F]F2. When large biological molecules, such as peptides, proteins, antibodies, or oligonucleotides, are to be labelled with fluorine- 18, true labelling is not an issue because these molecules do not possess fluorine atoms of their own. Click chemistry has become highly fashionable in 18F-positron emission tomography (PET) chemistry, especially in bioconjugation because of the mild reaction conditions in water or aqueous organic mixtures, the high yields, and the in vivo stability of the triazole entity, which mimics an amide or peptide bond, and the relative inertness of the azide and alkyne functions toward other reactions in the applied condition.

The TSPO (translocator protein), also known as the peripheral benzodiazepine receptor, is upregulated in the brain of subjects suffering from neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Moreover, this overexpression has been proved to be linked to microglia activation making thus the TSPO a marker of choice of neuroinflammatory processes and therefore a potential target for the development of radioligands for positron emission tomography imaging. The discovery of selective TSPO ligands and their labelling with the short-lived positron-emitter isotopes carbon-11 and fluorine-18 emerged in the mid-1980s with the preparation of the 3-isoquinolinecarboxamide [(11) C]PK11195. To date, an impressive number of promising compounds-[(11) C]PK11195-challengers-have been developed; some radioligands-for example, [(11) C]PBR28, [(11) C]DPA-713, [(18) F]FEDAA1106 and [(18) F]DPA-714-are currently used in clinical trials. As illustrated in this review, the methodologies applied for the preparation of these compounds remain mainly [(11) C]methylations using [(11) C]MeI or [(11) C]MeOTf and SN 2-type nucleophilic aliphatic [(18) F]fluorinations-two processes illustrating the state-of-the-art arsenal of reactions that involves these two short-lived radioisotopes-but alternative processes, such as [(11) C]carbonylations using [(11) C]CO and [(11) C]COCl2 as well as SN Ar-type nucleophilic [(18) F]fluorinations, have also been reported and as such, reviewed herein.

Fluorine-18 radiochemistry is an essential tool in Positron Emission Tomography, providing the bridge between the cyclotron-produced raw radioisotope and the biomedical image of an in vivo radioactivity distribution. From the fluorine-18 labelled radioligands for the translocator protein 18kDa that are produced in our laboratory, namely [18F]FEDAA1106, 6-[18F]F-PBR28, [18F]PBR111 and [18F]DPA-714, we address various aspects of fluorine-18 radiochemistry, such as rationales of radiotracer design, radioisotope production and [18F]fluoride activation, and procedures of radiofluorination, purification and formulation. Automation of the radiochemistry process has become indispensable in order to assure a constant radiopharmaceutical quality and reproducible radiochemical yields as well as to meet the required radiation protection aspects.

Neuroinflammation is a process characterised by drastic changes in microglial morphology and by marked upregulation of the 18-kDa translocator protein (TSPO) on the mitochondria. The continual increase in incidence of neuroinflammation and neurodegenerative diseases poses a major health issue in many countries, requiring more innovative diagnostic and monitoring tools. TSPO expression may constitute a biomarker for brain inflammation that could be monitored by using TSPO tracers as neuroimaging agents. From medical imaging perspectives, this review focuses on the current concepts related to the TSPO, and discusses briefly on the status of its PET imaging related to neuroinflammation and neurodegenerative diseases in humans.

[C-11] Phosgene has been playing a relatively modest but continuous and manifest role all along the history of radiochemistry for Positron Emission Tomography. It acts as a radiolabelling agent through carbonyl insertion, usually between heteroatoms, and benefits from a high chemical reactivity allowing for short reaction times. The aim of this review is to give an overview of this radiochemistry from its beginning until the present day. After drawing up the inventory of the various ways of its production, the reactions in which it has been employed and the labelled products that have been synthesised with it are catalogued. This comprises the reactions of [C-11] phosgene with primary, secondary and tertiary amines to labelled isocyanates and carbamoyl chlorides, which serve as intermediates for symmetrical and unsymmetrical [C-11] ureas and [C-11] carbamates, reactions with alcohols leading to labelled carbamates and carbonates via [C-11] chloroformates, cyclisation reactions to heterocycles and the radiochemistry of the secondary radiolabelling agents [C-11] urea and diethyl-or dimethyl [C-11] carbonate. Apart from this already vast field of chemical possibilities there should be room for extension of the use of [C-11] phosgene to other chemistry, notably that of C-C-11 bond formation.

A new flow-through system for the production of [C-11]phosgene, a versatile labelling agent in radiochemistry for PET, is described. Cyclotron-produced [C-11]CH4 is mixed with Cl-2 and converted into [C-11]CCl4 by passing the mixture through an empty quartz tube at 510 degrees C. The Outflow is directed through a Sb-filled guard that takes Out Cl-2 and then, without intentional O-2 addition, through a second empty quartz tube at 750 degrees C, giving rise to [C-11]phosgene in 30-35% radiochemical yield. (C) 2009 Elsevier Ltd. All rights reserved.

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/[F-18] fluoride in acetonitrile or DMSO. Competitive elimination can be a serious problem that can affect both yield and purification. De-protection 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 [F-18]FLT, whereas older concepts such as certain cyclic reactive entities for ring opening or even an abandoned reagent as [F-18]DAST should not be forgotten.

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-[F-18] fluoro-2-deoxy-D-glucose ([F-18]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 [F-18] 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) [F-18] fluoride as its K[F-18]F-K-222 complex and include S(N)2-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.

Molecular in vivo imaging with the high-resolution and sensitive positron emission tomography (PET) technique requires the preparation of positron-emitting radiolabelled probes or radiotracers. For this purpose, fluorine-18 is becoming increasingly the radionuclide of choice due to its adequate physical and nuclear characteristics(The successful use in clinical oncology of 2-[F-18]fluoro-2-deoxy-D-glucose ([F-18]FDG), currently the most widely used PET radiopharmaceutical, is manifestly also the motor behind the growing availability and interest for this positron emitter in radiopharmaceutical chemistry(The use of fluorine-18, however, presents some drawbacks, in particular the limited options in labelling strategies(Besides a few exceptions, radiofluorinations can be classified into two categories: nucleophilic and electrophilic reactions(The nucleophilic reactions usually involve no-carrier-added (high-specific-radioactivity) [F-18] fluoride as its K[F-18]F-K-222 complex and include S(N)2-type substitutions in the aliphatic series and SNAr-type substitutions in the homoaromatic and heteroaromatic (particularly the pyridine family) series(The electrophilic reactions mainly use molecular [F-18]fluorine of moderately low specific radioactivity, or reagents prepared from it such as acetyl [F-18]hypofluorite, and include additions across double bonds, reactions with carbanions and especially fluorodehydrogenation and fluorodemetallation, where tin clearly appears to be the metal of choice. This chapter presents the bases and some recent advances in the field of fluorine-18 radiochemistry and highlights the potential of this radioisotope in the design and preparation of fluorine18-labelled probes for PET imaging, often drug based but also macromolecules of biological interest such as peptides, proteins and oligonucleotides

The Service Hospitalier Frederic Joliot (SHFJ) (CEA-Orsay, France) has been a stimulating interdisciplinary research platform in medical imaging for almost half a century and particularly in the field of positron emission tomography (PET). In this context, PET chemistry, the driving force in molecular imaging, has occupied the front stage, especially where it concerns the short-lived radioisotopes carbon- 11 and fluorine-18. In this review, important marks left by the SHFJ actors over the years will be highlighted. Copyright (c) 2007 John Wiley & Sons, Ltd.

tween dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) is ofconsiderable impor tance given the increase in the numbers of demented patients in the developed world and the fact that ther apeutic trials for both DAT and MID are beginning to emerge. The appearances seen with @mTc@HMPAO SPECT in DAT patients are similar to those seen using positron emission tomography (PET) (6—9),which is, of course, a much more expensive and elaborate pro cedure and so unsuitable for routine clinical use. Despite the similarity between @mTc@HMPAO SPECT images and PET images in the demented pa tient, there is still a need to compare the data quanti tatively. Such a comparison will help both to validate 99mTcHMPAO and to show whether 99mTcHMPAO can be used to measure rCBF in absolute units. In this study, a quantitative method is used to compare rCBF images obtained using C1502 PET with images obtained using 99mTcHMPAO SPECT in a group of demented patients. The aimof thisstudywas to comparetechnetium-99mhexamethylpropyleneamineoxime (@Tc-HMPAO)single photon emission computed tomography (SPECT) with re gionalcerebralbloodflow (rCBF)imagingusingpositron emissiontomography (PET).Asinvestigation of dementia is likelyto beoneofthe mainusesof routinerCBFimaging, 18 demented patients were imaged with both techniques. The PET data were comparedquantitativelywith three versionsof the SPECTdata.Thesewere, first, data nor malizedto the SPECTcerebellaruptake, second,data linearlycorrected using the PET cerebellarvalue and, finally,data Lassencorrectedfor washoutfrom the high flow areas. Both the linearly-corrected(r = 0.81) and the Lassen-corrected(r = 0.79)HMPAOSPECTdatashowed good correlation with the PET rCBF data. The relationship betweenthe normalizedHMPAOSPECTdata and the PETdatawas nonlinear. It is notyet possibleto obtain rCBF values in absolute units from HMPAO SPECT with out knowledgeof the true rCBF in one referenceregion for eachpatient.

The reduction of [C-11]carbon dioxide to [C-11]methanol with lithium aluminium hydride (LiAlH4) and subsequent conversion into [C-11]methyl iodide is a standard way of producing the latter precursor for radiolabelling. However, it suffers from appreciable losses by incomplete reduction giving [C-11]formate. We show that samarium diiodide (SmI2) can be used to improve the yield of [C-11]methanol by its ability to efficiently reduce [C-11]formate to [C-11]methanol. This can be done either by making [C-11]formate intentionally and treating it with SmI2 or by treating the LiAlH4-reduced [C-11]CO2 with SmI2. In the latter approach, sodium thiosulphate has a similar effect as SmI2. Hydriodic acid was also shown to exert some reducing action on [C-11]formate too. [C-11]Carbonate is reduced to a small extent by SmI2 under the mild conditions employed. In contrast to the very easy [C-11]formate reduction, SmI2 had little effect on [C-11]acetate and practically no [C-11]ethanol could be produced. Copyright (c) 2006 John Wiley & Sons, Ltd.

1,1'-Methylene-di-(2-naphthol) (ST1859), a candidate drug for the treatment of Alzheimer's disease, was radiolabelled with carbon-11 with the aim to perform PET microdosing studies in humans. The radiosynthesis was automated in a commercial synthesis module (Nuclear Interface PET tracer synthesizer) and proceeded via reaction of [C-11]formaldehyde with 2-naphthol. [C-11]formaldehyde was prepared by catalytic dehydrogenation of [C-11]methanol (conversion yield: 48 +/- 11 % (n = 19)) employing a recently developed silver-containing ceramic catalyst. Starting from 69 +/- 3 GBq of [C-11]carbon dioxide (n = 19), 4 +/- 1 GBq of [C-11]ST1859 (decaycorrected to the end of bombardment), readily formulated for intravenous administration, could be obtained in an average synthesis time of 38 min. The specific radioactivity of [C-11]ST1859 at the end of synthesis exceeded 32 GBq/ mu mol. Copyright (c) 2005 John Wiley & Sons, Ltd.