Search

A copper‐catalysed radiosynthesis of carbon‐11 radiolabelled carboxylic acids was developed by reacting terminal alkynes and cyclotron‐produced carbon‐11 carbon dioxide ([11C]CO2) in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). A small library of 11C‐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%. [ABSTRACT FROM AUTHOR]

A copper‐catalysed radiosynthesis of carbon‐11 radiolabelled carboxylic acids was developed by reacting terminal alkynes and cyclotron‐produced carbon‐11 carbon dioxide ([11C]CO2) in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU). A small library of 11C‐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%. [ABSTRACT FROM AUTHOR]

[11C]Carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]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 11C‐labelled compounds is required to enhance the radiotracers available for positron emission tomography, molecular, and medical imaging applications. Following a brief summary of secondary 11C‐precursor production and uses, the review focuses on recent progress with direct 11C‐carboxylation routes with [11C]CO2 and 11C‐carbonylation with [11C]CO. Novel approaches to generate [11C]CO using CO‐releasing molecules (CO‐RMs), such as silacarboxylic acids and disilanes, applied to radiochemistry are described and compared with standard [11C]CO production methods. These innovative [11C]CO synthesis strategies represent efficient and reliable [11C]CO production processes, enabling the widespread use of [11C]CO chemistry within the wider radiochemistry community. [ABSTRACT FROM AUTHOR]

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 ([11C]CO2), which is most commonly converted into a more reactive precursor for synthesis of PET radiotracers. The development of [11C]CO2 fixation methods has more recently enabled the direct radiolabelling of a diverse array of structures directly from [11C]CO2, and the advantages afforded by the use of a loop‐based system used in 11C‐methylation and 11C‐carboxylation reactions inspired us to apply the [11C]CO2 fixation “in‐loop.” In this work, we developed and investigated a new ethylene tetrafluoroethylene (ETFE) loop‐based [11C]CO2 fixation method, enabling the fast and efficient, direct‐from‐cyclotron, in‐loop trapping of [11C]CO2 using mixed DBU/amine solutions. An optimised protocol was integrated into a proof‐of‐concept in‐loop flow radiosynthesis of N,N′‐[11C]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 [11C]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 [11C]CO2 trapping/fixation reactions for the production of PET radiotracers. [ABSTRACT FROM AUTHOR]

Here we present a new Michael addition reaction utilizing carbon-11 labeled acrylic esters and amides. Subsequently, reactions of these synthons with commercially available Schiff base precursors are performed to produce [11C]- glutamate and [11C]glutamine. This methodology is especially useful for the development of positron emission tomography (PET) imaging agents as it offers a new array of potential carbon-11 labeled compounds with this original 11C-C bond forming strategy. [ABSTRACT FROM AUTHOR]

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

The copper(I) coordination chemistry of tris(3-R-5-R′-pyrazolyl)borate ligands (TpR,R′) bearing substituent groups attached to the pyrazole rings has been investigated under nitrogen and carbon monoxide atmospheres [ 1 (TpPh,SMe) R = Ph, R′ = SCH3; 2 (TpPy) R = 2-pyridyl, R′ = H; 3 (TpPhos,Me) R = 2-(diphenylphosphinyl)phenyl, R′ = CH3]. The reactivity is strongly dependent on the coordinating potential of the substituent groups; in the absence of CO, 1 formed an insoluble complex [Cu(TpPh,SMe)] n ( 1b), 2 formed a multinuclear species [Cu(TpPy)] n ( 2a; tetrameric in solution, dimeric in the solid state) and 3 formed a discrete complex [Cu(TpPhos,Me)] ( 3a). Under a CO atmosphere, 1 displayed irreversible CO binding to form the complex [Cu(TpPh,SMe)CO] ( 1c), 2 showed reversible CO binding between 2a and the mononuclear species [Cu(TpPy)CO] ( 2b), and 3 did not bind to CO, but instead formed 3a. The reactivity of the copper complexes of 1 and 2 with [11C]carbon monoxide has been examined in the radiochemistry laboratory to investigate the reversibility of 11CO binding. The solid-state structures of [Tl(TpPh,SMe)] ( 1a), 1c and 2a were elucidated by X-ray crystallography. [ABSTRACT FROM AUTHOR]

Palladium(II)-mediated oxidative carbonylation reactions have been used to synthesize 11C-radiolabelled ureas via the coupling of amines with [11C]carbon monoxide, in a one-pot process. Following trapping of 11CO in a solution of copper(I) tris(3,5-dimethylpyrazolyl)borate, homocoupling reactions of primary aliphatic amines proceed in the presence of Pd(PPh3)2Cl2 to give the corresponding N, N-disubstituted [11C]ureas. Secondary amines do not produce the corresponding N, N, N, N-tetrasubsituted [11C]ureas under these conditions. This difference in reactivity allows for the formation of unsymmetrical N, N', N'-trisubstituted [11C]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, [11C- carbonyl]GSK1034702. [ABSTRACT FROM AUTHOR]

Meeting Summary The 21st annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday 12th October 2012. The meeting was attended by around 60 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds or of chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Professor Chris Willis (University of Bristol, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Sofia Pascu (University of Bath, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, Stevenage, UK). [ABSTRACT FROM AUTHOR]

Performing gold-catalyzed organic transformations in the presence of fluorinating reagents can lead to both fluorinated and non-fluorinated products. Gold(I) complexes can activate alkynes towards nucleophilic attack by fluoride leading to fluoroalkenes under mild conditions. Fluorinated products can also be prepared upon performing gold-catalyzed transformations in the presence of electrophilic sources of fluorine. In most cases, however, the combination of gold and electrophilic fluorinating reagents does not lead to fluorination but delivers products of oxidative homo- or cross-coupling. In these processes the 'F' source is likely acting as a sacrificial two-electron external oxidant performing the key oxidation of gold(I) to gold(III) in the redox cycle. Oxidative coupling is an emerging field of gold catalysis which, when combined with the well-established reactivity of gold as a soft π-acid, holds promise as a mild and efficient method for the construction of complex organic molecules. [ABSTRACT FROM AUTHOR]

Nonspecific binding is a poorly understood biological phenomenon of relevance in the study of small molecules interactions in vivo and in drug development. Nonspecific binding is thought to be correlated in part to a molecule's lipophilicity, typically estimated by measuring (or calculating) octanol–water partition coefficient. This is, however, a gross simplification of a complex phenomenon. In this article, we present a computational method whose aim is to help identify positron emission tomography (PET) ligands with low nonspecific binding characteristics by investigating the molecular basis of ligand–membrane interaction. We considered a set consisting of 10 well-studied central nervous system PET radiotracers acting on a variety of molecular targets. Quantum mechanical calculations were used to estimate the strength of the interaction between each drug molecule and one phospholipid molecule commonly present in mammalian membranes. The results indicate a correlation between the computed drug–lipid interaction energy and the in vivo nonspecific distribution volume relative to the free tracer plasma concentration, calculated using standard compartmental modeling for the analysis of PET data. Significantly, the drugs whose interaction with the lipid molecule more favorably possessed, in general, a higher nonspecific binding value, whereas for the drugs taken in consideration in this study, the water-octanol partition coefficient, log P, did not show good predictive power of the nonspecific binding. This study also illustrates how ab initio chemical methods may offer meaningful and unbiased insights for the understanding of the underlying chemical mechanisms in biological systems. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2008 [ABSTRACT FROM AUTHOR]

Based largely on in vitro measurements, the mechanism of several antidepressant treatments is thought to involve upregulation of 3′-5′-cyclic adenosine monophosphate (cAMP) signal transduction cascade and a corresponding increase in phosphodiesterase (PDE) 4, the enzyme that metabolizes cAMP. To assess the in vivo status of PDE4, rats were chronically treated with imipramine and then studied with: (1) in vivo positron emission tomography (PET) measurement of ( R)-[11C]rolipram binding, (2) in vitro measurement of [3H]rolipram binding in brain homogenates, and (3) Western blotting for protein levels of PDE4 isoforms. Imipramine administration caused no significant change in Bmax/ Kd, for both in vivo measurements with ( R)-[11C]rolipram and in vitro measurements with [3H]rolipram in frontal cortex, hippocampus, and diencephalon. None of 10 isoforms of PDE4A, B, and D measured with immunoblots of frontal cortex and hippocampus showed a significant change. In summary, using relatively large brain regions for both in vivo imaging and in vitro measures of radiolabeled ligand binding and protein levels, chronic imipramine treatment via continuous mini-pump administration caused no significant change in PDE4 levels. Most, but not all, prior in vitro studies have found increased PDE4 levels after antidepressant administration. The current results raise questions about the in vivo effects of antidepressant treatment on PDE4 and on other potentially important experimental factors (e.g., continuous infusion vs. intermittent injection of antidepressant) in large brain areas. However, the results do not deny possibility of changes in discrete areas, which were not studied in the current study applying PET. Synapse 61:78-86, 2007. Published 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Cyclic AMP (cAMP) is a continually produced nucleotide which is inactivated by hydrolysis to 5′AMP via phosphodiesterase 4 (PDE4) enzymes. Rolipram is a selective PDE4 inhibitor which exists in two enantiomeric forms, R(−) and S(+). Both of these enantiomers have previously been labelled with carbon-11 and used as positron emission tomography (PET) ligands for measuring PDE4 expression and function, and indirectly to explore the function of the cAMP second messenger, in vivo, using PET. The aim of these studies was to relate the in vitro affinities of the two rolipram enantiomers using standard pharmacological assays with the in vivo behaviour of the two enantiomers using PET. In vitro competition assays were performed using rat cortical membranes and [3H] R(−)- and [3H] S(+)-rolipram with increasing concentrations of either unlabelled R(−)- or S(+)-rolipram. In vivo, a series of PET studies were performed in the porcine brain using [11C] R(−)-rolipram with co-administration of increasing doses of either unlabelled R(−)- or S(+)-rolipram. Additional in vivo PET studies were performed using [11C] S(+)-rolipram with saturating doses of rolipram. In all studies, R(−)-rolipram exhibited a higher affinity for the PDE4 enzyme than S(+)-rolipram. The calculated affinity ratios were 7.97 from the in vitro studies; 12.5 from the in vivo studies using [11C] R(−)-rolipram; and 14.7 from the in vivo studies using [11C] S(+)-rolipram. To conclude, the in vitro affinities of R(−)- and S(+)-rolipram predict their apparent in vivo behaviour in the porcine brain, as measured by PET. Synapse 55:270-279, 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

An introduction to the issue, which is themed on radiochemistry professor Bengt Långström, and discusses Långström's life, including his work on topics including producing the carbon-11 isotope.