Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds.

The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

Silicon compounds in carbon-11 radiochemistry: present use and future perspectives.

Positron emission tomography (PET) is a powerful functional imaging technique that requires the use of positron emitting nuclides. Carbon-11 (11C) radionuclide has several advantages related to the ubiquity of carbon atoms in biomolecules and the conservation of pharmacological properties of the molecule upon isotopic exchange of carbon-12 with carbon-11. However, due to the short half-life of 11C (20.4 minutes) and the low scale with which it is produced by the cyclotron (sub-nanomolar concentrations), quick, robust and chemospecific radiolabelling strategies are required to minimise activity loss during incorporation of the 11C nuclide into the final product. To address some of the constraints of working with 11C, the use of silicon-based chemistry for 11C-labelling was proposed as a rapid and effective route for radiopharmaceutical production due to the broad applicability and high efficiency showed in organic chemistry. In the past years several organic chemistry methodologies have been successfully applied to 11C-chemistry. In this short review, we examine silicon-based 11C-chemistry, with a particular emphasis on the radiotracers that have been successfully produced and potential improvements to further expand the applicability of silicon in radiochemistry.

Carbon-11 carboxylation of terminal alkynes with [11 C]CO2.

A copper-catalysed radiosynthesis of carbon-11 radiolabelled carboxylic acids was developed by reacting terminal alkynes and cyclotron-produced carbon-11 carbon dioxide ([11 C]CO2 ) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). A small library of 11 C-labelled propiolic acid derivatives were obtained with a total synthesis time of 15 min from end of bombardment (EOB) with a (non-isolated) radiochemical yield ranging from 7% to 28%.

Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions.

This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.

Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs.

Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.

Recent progress in [11 C]carbon dioxide ([11 C]CO2 ) and [11 C]carbon monoxide ([11 C]CO) chemistry.

[11 C]Carbon dioxide ([11 C]CO2 ) and [11 C]carbon monoxide ([11 C]CO) are 2 attractive precursors for labelling the carbonyl position (C═O) in a vast range of functionalised molecules (eg, ureas, amides, and carboxylic acids). The development of radiosynthetic methods to produce functionalised 11 C-labelled compounds is required to enhance the radiotracers available for positron emission tomography, molecular, and medical imaging applications. Following a brief summary of secondary 11 C-precursor production and uses, the review focuses on recent progress with direct 11 C-carboxylation routes with [11 C]CO2 and 11 C-carbonylation with [11 C]CO. Novel approaches to generate [11 C]CO using CO-releasing molecules (CO-RMs), such as silacarboxylic acids and disilanes, applied to radiochemistry are described and compared with standard [11 C]CO production methods. These innovative [11 C]CO synthesis strategies represent efficient and reliable [11 C]CO production processes, enabling the widespread use of [11 C]CO chemistry within the wider radiochemistry community.

In-loop flow [11 C]CO2 fixation and radiosynthesis of N,N'-[11 C]dibenzylurea.

Cyclotron-produced carbon-11 is a highly valuable radionuclide for the production of positron emission tomography (PET) radiotracers. It is typically produced as relatively unreactive carbon-11 carbon dioxide ([11 C]CO2 ), which is most commonly converted into a more reactive precursor for synthesis of PET radiotracers. The development of [11 C]CO2 fixation methods has more recently enabled the direct radiolabelling of a diverse array of structures directly from [11 C]CO2 , and the advantages afforded by the use of a loop-based system used in 11 C-methylation and 11 C-carboxylation reactions inspired us to apply the [11 C]CO2 fixation "in-loop." In this work, we developed and investigated a new ethylene tetrafluoroethylene (ETFE) loop-based [11 C]CO2 fixation method, enabling the fast and efficient, direct-from-cyclotron, in-loop trapping of [11 C]CO2 using mixed DBU/amine solutions. An optimised protocol was integrated into a proof-of-concept in-loop flow radiosynthesis of N,N'-[11 C]dibenzylurea. This reaction exhibited an average 78% trapping efficiency and a crude radiochemical purity of 83% (determined by radio-HPLC), giving an overall nonisolated radiochemical yield of 72% (decay-corrected) within just 3 minutes from end of bombardment. This proof-of-concept reaction has demonstrated that efficient [11 C]CO2 fixation can be achieved in a low-volume (150 µL) ETFE loop and that this can be easily integrated into a rapid in-loop flow radiosynthesis of carbon-11-labelled products. This new in-loop methodology will allow fast radiolabelling reactions to be performed using cheap/disposable ETFE tubing setup (ideal for good manufacturing practice production) thereby contributing to the widespread usage of [11 C]CO2 trapping/fixation reactions for the production of PET radiotracers.

Instantaneous Conversion of [11 C]CO2 to [11 C]CO via Fluoride-Activated Disilane Species.

The development of a fast and novel methodology to generate carbon-11 carbon monoxide ([11 C]CO) from cyclotron-produced carbon-11 carbon dioxide ([11 C]CO2 ) mediated by a fluoride-activated disilane species is described. This methodology allows up to 74 % conversion of [11 C]CO2 to [11 C]CO using commercially available reagents, readily available laboratory equipment and mild reaction conditions (room temperature). As proof of utility, radiochemically pure [carbonyl-11 C]N-benzylbenzamide was successfully synthesized from produced [11 C]CO in up to 74 % radiochemical yield (RCY) and >99 % radiochemical purity (RCP) in ≤10 min from end of [11 C]CO2 delivery.

(11)C[double bond, length as m-dash]O bonds made easily for positron emission tomography radiopharmaceuticals.

The positron-emitting radionuclide carbon-11 ((11)C, t1/2 = 20.3 min) possesses the unique potential for radiolabeling of any biological, naturally occurring, or synthetic organic molecule for in vivo positron emission tomography (PET) imaging. Carbon-11 is most often incorporated into small molecules by methylation of alcohol, thiol, amine or carboxylic acid precursors using [(11)C]methyl iodide or [(11)C]methyl triflate (generated from [(11)C]carbon dioxide or [(11)C]methane). Consequently, small molecules that lack an easily substituted (11)C-methyl group are often considered to have non-obvious strategies for radiolabeling and require a more customized approach. [(11)C]Carbon dioxide itself, [(11)C]carbon monoxide, [(11)C]cyanide, and [(11)C]phosgene represent alternative reactants to enable (11)C-carbonylation. Methodologies developed for preparation of (11)C-carbonyl groups have had a tremendous impact on the development of novel PET tracers and provided key tools for clinical research. (11)C-Carbonyl radiopharmaceuticals based on labeled carboxylic acids, amides, carbamates and ureas now account for a substantial number of important imaging agents that have seen translation to higher species and clinical research of previously inaccessible targets, which is a testament to the creativity, utility and practicality of the underlying radiochemistry.

Guidelines to PET measurements of the target occupancy in the brain for drug development.

This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations.

EANM guideline for the preparation of an Investigational Medicinal Product Dossier (IMPD).

The preparation of an Investigational Medicinal Product Dossier (IMPD) for a radiopharmaceutical to be used in a clinical trial is a challenging proposition for radiopharmaceutical scientists working in small-scale radiopharmacies. In addition to the vast quantity of information to be assembled, the structure of a standard IMPD is not well suited to the special characteristics of radiopharmaceuticals. This guideline aims to take radiopharmaceutical scientists through the practicalities of preparing an IMPD, in particular giving advice where the standard format is not suitable. Examples of generic IMPDs for three classes of radiopharmaceuticals are given: a small molecule, a kit-based diagnostic test and a therapeutic radiopharmaceutical.

One-pot multi-tracer synthesis of novel (18)F-labeled PET imaging agents.

(18)F labeled phosphonium salts are increasingly important molecular probes for targeting the mitochondrial membrane potential depletion during apoptosis and for detecting myocardial perfusion deficit. Here, we introduce three new tracers, [(18)F]MitoPhos_04, [(18)F]MitoPhos_05, and [(18)F]MitoPhos_07, that have the potential to act as mitochondrial imaging agents. Moreover, they have the added advantage of being synthesized in the same reaction vial from one radiolabeled synthon, demonstrating a new approach to synthesizing multiple tracers in one-pot, which is a highly useful means for increasing the throughput of radiotracer development. The radiosynthesis of the tracers was carried out on a fully automated system via a facile two-step reaction. Utilizing the radiolabeling of an ethyl azide, a copper-mediated 1,3-cycloaddition reaction and isolation via semiprep high-performance liquid chromatography (HPLC) allowed for the simultaneous synthesis of two or three tracers with a total synthesis time of less than 1 h.

Transition metal mediated [(11) C]carbonylation reactions: recent advances and applications.

[(11) C]Carbon monoxide is undoubtedly a highly versatile radiolabelling synthon with many potential applications for the synthesis of positron emission tomography (PET) tracer molecules and functional groups, but why has it not found more applications in the PET radiolabelling arena? Today, (11) CO radiolabelling is still primarily viewed as a niche area; however, there are signs that this is beginning to change as some of the technical and chemistry challenges of producing, handling and reacting (11) CO are overcome. This mini review covers the more recent developments of (11) CO-labelling chemistry and is focused on palladium and rhodium-mediated carbonylation reactions that are growing in importance and finding wider application for carbon-11 PET radiotracer development.

Palladium-mediated oxidative carbonylation reactions for the synthesis of (11) C-radiolabelled ureas.

Palladium(II)-mediated oxidative carbonylation reactions have been used to synthesize (11) C-radiolabelled ureas via the coupling of amines with [(11) C]carbon monoxide, in a one-pot process. Following trapping of (11) CO in a solution of copper(I) tris(3,5-dimethylpyrazolyl)borate, homocoupling reactions of primary aliphatic amines proceed in the presence of Pd(PPh3 )2 Cl2 to give the corresponding N,N-disubstituted [(11) C]ureas. Secondary amines do not produce the corresponding N,N,N,N-tetrasubsituted [(11) C]ureas under these conditions. This difference in reactivity allows for the formation of unsymmetrical N,N',N'-trisubstituted [(11) C]ureas using a mixture of a primary amine and a reactive secondary amine. The potential use of this method in positron emission tomography (PET) was demonstrated by the synthesis of the M1 muscarinic acetylcholine receptor radiotracer, [(11) C-carbonyl]GSK1034702.

Pyridine-based strategies towards nitrogen isotope exchange and multiple isotope incorporation.

Isotopic labeling is at the core of health and life science applications such as nuclear imaging, metabolomics and plays a central role in drug development. The rapid access to isotopically labeled organic molecules is a sine qua non condition to support these societally vital areas of research. Based on a rationally driven approach, this study presents an innovative solution to access labeled pyridines by a nitrogen isotope exchange reaction based on a Zincke activation strategy. The technology conceptualizes an opportunity in the field of isotope labeling. 15N-labeling of pyridines and other relevant heterocycles such as pyrimidines and isoquinolines showcases on a large set of derivatives, including pharmaceuticals. Finally, we explore a nitrogen-to-carbon exchange strategy in order to access 13C-labeled phenyl derivatives and deuterium labeling of mono-substituted benzene from pyridine-2H5. These results open alternative avenues for multiple isotope labeling on aromatic cores.

Fully automated radiosynthesis of [1-(2-[18 F]fluoroethyl),1H[1,2,3]triazole 4-ethylene] triphenylphosphonium bromide as a potential positron emission tomography tracer for imaging apoptosis.

A novel phosphonium salt bearing a fluorine-18 labelled triazole has been designed as a potential imaging agent for apoptosis. The radiosynthesis of [1-(2-[(18)F]fluoroethyl),1H[1,2,3]triazole 4-ethylene] triphenylphosphonium bromide ([(18)F]MitoPhos_01) has been carried out on a fully automated system in a two-step reaction. Radiolabelling an ethyl azide and then carrying out a copper-mediated 1,3-cycloaddition reaction has allowed for total synthesis time to be slightly more than 1 h from aqueous [(18)F]fluoride. After purification by HPLC, the average radiochemical yield was determined to be 9% (not decay corrected); the specific activity was on average 70 GBq/µmol at the end of synthesis, and the radiochemical purity was >99%.

A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases.

The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - the major excitatory neurotransmitter in the mammalian brain. EAAT2 loss/dysfunction triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for ALS and AD. This perspective article describes the role of EAAT2 in physio/pathological processes and provides a structure-activity relationship of EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis (molecular imaging tools).