Dirk Roeda

Current paradigm of the 18-kDa translocator protein (TSPO) as a molecular target for PET imaging in neuroinflammation and neurodegenerative diseases

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.

An improvement of 11C acetate synthesis--non-radioactive contaminants by irradiation-induced species emanating from the 11C carbon dioxide production target.

An existing procedure for [11C]acetate synthesis, consisting of a reaction of methylmagnesium chloride and [11C]carbon dioxide in tetrahydrofuran, hydrolysis and ion-exchange purification on small columns, has been improved. The use of less Grignard reagent and application of commercial cartridges instead of home made ones led to an increase of the overall yield from 60-65% to over 80%. Malfunction in pure nitrogen targets for 11C production may lead to unexpected contaminants. It is recommended to incorporate in the target outlet line a trap for removal of nitrogen oxides.

The potential of carbon‐11 and fluorine‐18 chemistry: illustration through the development of positron emission tomography radioligands targeting the translocator protein 18 kDa

The TSPO (translocator protein), also known as the peripheral benzodiazepine receptor, is upregulated in the brain of subjects suffering from neurodegenerative disorders such as Alzheimers, Parkinsons and Huntingtons 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.

[11C]Phosgene: A Versatile Reagent for Radioactive Carbonyl Insertion Into Medicinal Radiotracers for Positron Emission Tomography

: [¹¹C]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 [¹¹C]phosgene with primary, secondary and tertiary amines to labelled isocyanates and carbamoyl chlorides, which serve as intermediates for symmetrical and unsymmetrical [¹¹C]ureas and [¹¹C]carbamates, reactions with alcohols leading to labelled carbamates and carbonates via [¹¹C]chloroformates, cyclisation reactions to heterocycles and the radiochemistry of the secondary radiolabelling agents [¹¹C]urea and diethyl- or dimethyl [¹¹C]carbonate. Apart from this already vast field of chemical possibilities there should be room for extension of the use of [¹¹C]phosgene to other chemistry, notably that of C-¹¹C bond formation.

Fluorine-18 Chemistry for PET: A Concise Introduction

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.

Fluorine‐18 Chemistry for Molecular Imaging with Positron Emission Tomography

Publisher Summary Positron emission tomography (PET) is a high-resolution, sensitive, functional-imaging technique in nuclear medicine that permits repeated, non-invasive assessment, and quantification of specific biological and pharmacological processes at the molecular level in humans and animals. It is the most advanced technology currently available for studying in vivo molecular interactions in terms of distribution, pharmacokinetics, and pharmacodynamics. Molecular PET imaging requires the preparation of a positron-emitting radiolabeled probe or radiotracer. For this purpose, fluorine-18 is becoming increasingly the radionuclide of choice not only due to its adequate physical and nuclear characteristics but also due to the successful use in clinical oncology of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), currently the most widely used PET radiopharmaceutical and manifestly a motor behind the growing availability and interest for this positron emitter in radiopharmaceutical chemistry. This chapter addresses this complex interdisciplinary and rapidly growing field from a radiochemist point of view, focusing on the synthesis of fluorine-18-labelled radiopharmaceuticals. The successful use in clinical oncology of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]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 labeling strategies. The synthesis of complex structures labeled with fluorine-18 remains a challenge but undoubtedly, fluorine-18 is already, and will continue to be, a royal gateway to success in molecular imaging with PET.

[11C]Formaldehyde revisited: considerable concurrent [11C]formic acid formation in the low-temperature conversion of [11C]carbon dioxide into [11C]formaldehyde

The reduction of [11C]carbon dioxide with lithium aluminium hydride in diethyl ether at temperatures ranging from -56 degrees C to 19 degrees C was studied. In contrast to what others have reported, considerable amounts of [11C]formic acid were found at all studied temperatures.

Synthesis of [11C]RPR-72840A and its evaluation as a radioligand for the serotonin reuptake site in positron emission tomography.

RPR-72840A, an inhibitor of serotonin reuptake, was labelled with carbon-11. The synthesis of the nonradioactive precursor, which exhibited some unexpected chemistry, and its reaction with [11C]phosgene affording [11C]RPR-72840A are described. Biodistribution studies in rats and PET studies in baboons were conducted to evaluate [11C]RPR-72840A as a tracer for PET imaging of the serotonin reuptake system.

A rapid, almost quantitative conversion of [11C]carbon dioxide into [11C]carbon monoxide via [11C]formate and [11C]formyl chloride

Abstract [11C]Formic acid can be produced from no-carrier-added [11C]carbon dioxide reliably and instantaneously in almost quantitative radiochemical yield using lithium triethylborohydride in THF. It can react, either on a solid support or as its non-hydrolysed LiEt3B-adduct, with a complex formed from hexachloroacetone and triphenylphosphine in THF at room temperature to give, again almost quantitatively, [11C]formyl chloride. The latter decomposes instantaneously to give [11C]carbon monoxide, providing an interesting alternative for current methods of [11C]carbon monoxide production in radiopharmaceutical chemistry. [11C]Formyl chloride has also potential in low-temperature N-formylation.

The potential of carbon-11 and fluorine-18 chemistry: illustration through the development of positron emission tomography radioligands targeting the translocator protein 18 kDa: Carbon-11/fluorine-18 chemistry devoted to the preparation of TSPO 18 kDa PET-radioligands

The TSPO (translocator protein), also known as the peripheral benzodiazepine receptor, is upregulated in the brain of subjects suffering from neurodegenerative disorders such as Alzheimers, Parkinsons and Huntingtons 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.