Browsing by Author "Massi, M"
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- Item[18F]Ethenesulfonyl fluoride as a practical radiofluoride relay reagent(John Wiley & Sons, Inc, 2019-04-11) Zhang, B; Fraser, BH; Klenner, MA; Chen, Z; Liang, SH; Massi, M; Robinson, AJ; Pascali, GFluorine-18 is the most utilized radioisotope in positron emission tomography (PET), but the wide application of fluorine-18 radiopharmaceuticals is hindered by its challenging labelling conditions. As such, many potentially important radiotracers remain underutilized. Herein, we describe the use of [18F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres. [18F]ESF has a simple and reliable production route and can be stored on inert cartridges. The cartridges can then be shipped remotely and the trapped [18F]ESF can be liberated by simple solvent elution. We have tested 18 radiolabelling precursors, inclusive of model and clinically used structures, and most precursors have demonstrated comparable radiofluorination efficiencies to those obtained using a conventionally dried [18F]fluoride source. © 2019 Wiley-VCH Verlag GmbH & Co.
- ItemEffect of rhenium(i) complexation on aza-Michael additions to 5-amino-1,10-phenanthroline with [18F]ethenesulfonyl fluoride towards PET optical tracer development(CSIRO Publishing, 2019-01-14) Klenner, MA; Pascali, G; Zhang, B; Ciancaleoni, G; Massi, M; Fraser, BHConjugations with the recently developed [18F]ethenesulfonyl fluoride ([18F]ESF) were performed on 5-amino-1,10-phenanthroline, in its free form and coordinated to a rhenium(i) tricarbonyl complex, as a means of radiosynthesizing dual-modal optical and positron emission tomography (PET) tracers. The Michael-donating ability of the aromatic amine was noticeably perturbed on coordination with the rhenium(i) centre, resulting in decreased radiochemical yields from 34 %, in the case of the free ligand, to 1 %. We attribute the decreased nucleophilicity of the amine to metal deactivation from the electron-withdrawing feature of the rhenium(i) tricarbonyl centre, based on spectroscopic and computational evidence, thus highlighting this effect as a crucial parameter in designing late-stage metal coordination methods employing related aza-Michael additions. Photophysical analyses were also performed on the ESF-conjugated rhenium(i) complex, exhibiting a longer decay lifetime from the triplet metal-to-ligand charge transfer excited state when compared with the non-conjugated analogue. © CSIRO 1996-2021
- ItemA fluorine-18 radiolabeling method enabled by rhenium(I) complexation circumvents the requirement of anhydrous conditions(John Wiley & Sons, Inc, 2017-03-22) Klenner, MA; Pascali, G; Zhang, B; Sia, TR; Spare, LK; Krause-Heuer, AM; Aldrich-Wright, JR; Greguric, I; Guastella, AJ; Massi, M; Fraser, BHAzeotropic distillation is typically required to achieve fluorine-18 radiolabeling during the production of positron emission tomography (PET) imaging agents. However, this time-consuming process also limits fluorine-18 incorporation, due to radioactive decay of the isotope and its adsorption to the drying vessel. In addressing these limitations, the fluorine-18 radiolabeling of one model rhenium(I) complex is reported here, which is significantly improved under conditions that do not require azeotropic drying. This work could open a route towards the investigation of a simplified metal-mediated late-stage radiofluorination method, which would expand upon the accessibility of new PET and PET-optical probes. © 2017 John Wiley & Sons, Inc
- ItemIonophoric properties of a tetra-tetrazole functionalised calix[4]arene(Taylor and Francis Group, 2015-10-23) D'Alessio, D; Skelton, BW; Lengkeek, NA; Fraser, BH; Krause-Heuer, AM; Muzzioli, S; Stagni, S; Massi, M; Ogden, MIThe synthesis and characterisation of p-t-butylcalix[4]arene functionalised at the lower rim with four tetrazole moieties is reported. The macrocycle is found to be a poorer ionophore for lanthanoid cations than the bis-tetrazole–substituted analogue. Solution-phase photophysical studies strongly suggested that the cations interacted only weakly with the calixarene ligand. A mixed sodium/triethylammonium salt of the calixarene ligand was crystallised in the presence of lanthanoid cations and structurally characterised. Strong intramolecular interactions are hypothesised to be the cause of the observed behaviour. © 2015 Taylor & Francis
- ItemLabeled rhenium complexes: radiofluorination, α-MSH cyclization, and deuterium substitutions(American Chemical Society, 2020-06-19) Klenner, MA; Darwish, TA; Fraser, BH; Massi, M; Pascali, GWhile radiopharmaceuticals incorporating rhenium-188 or rhenium-186 radioisotopes have been well documented in the literature, the labeling of rhenium complexes with alternative isotopes has received comparatively less attention. Such rhenium complexes have demonstrated significant utility in imaging melanoma tumors via complexation with α-melanocyte-stimulating hormone (α-MSH) analogues conjugated with radiometals and radiohalogens, improving fluorine-18 incorporation into ligands which were otherwise unable to be synthesized and elucidating improved understandings of rhenium mechanisms and coordination sites through deuterium incorporation. This review highlights each of these rhenium-labeling cases and discusses the benefits derived therein, thus providing a useful resource for researchers intending to label unique rhenium complexes. © 2020 American Chemical Society
- ItemLanthanoid complexation by a tris-tetrazole-functionalised calix[4]arene(John Wiley & Sons, Inc, 2016-12-19) D'Alessio, D; Skelton, BW; Sobolev, AN; Krause-Heuer, AM; Fraser, BH; Massi, M; Ogden, MIThe synthesis and characterization of 5,11,17,23-tetra-tert-butyl-25-hydroxy-26,27,28-tris(tetrazol-5-ylmethoxy)calix[4]arene is reported. Purification of the macrocycle required the use of preparative HPLC techniques. The macrocycle was found to be a poorer ligand for complexation of lanthanoid cations than the bis(tetrazole) analogue, but somewhat more effective than the tetrakis(tetrazole)-substituted derivative. Two metal complexes of the tris(tetrazole)–calixarene were structurally characterised. A polymeric sodium salt of the tris(tetrazole)–calixarene was isolated from a solution containing yttrium and a sodium acetate buffer. A praseodymium complex was isolated in the presence of an ammonium acetate buffer, where the calixarene acts as a unidentate ligand, bound to the metal atom through one tetrazole N-atom. Increasing the amount of buffer resulted in the crystallisation of a metal-free ammonium salt of the calixarene. © 2016 John Wiley & Sons, Inc.
- ItemLanthanoid “bottlebrush” clusters: remarkably elongated metal–oxo core structures with controllable lengths(Journal of the American Chemical Society, 2014-10-04) D'Alessio, D; Sobolev, AN; Skelton, BW; Fuller, RO; Woodward, RC; Lengkeek, NA; Fraser, BH; Massi, M; Ogden, MILarge metal–oxo clusters consistently assume spherical or regular polyhedral morphologies rather than high-aspect-ratio structures. Access to elongated core structures has now been achieved by the reaction of lanthanoid salts with a tetrazole-functionalized calixarene in the presence of a simple carboxylate co-ligand. The resulting Ln19 and Ln12 clusters are constructed from apex-fused Ln5O6 trigonal bipyramids and are formed consistently under a range of reaction conditions and reagent ratios. Altering the carboxylate co-ligand structure reliably controls the cluster length, giving access to a new class of rod-like clusters of variable length. © 2014 American Chemical Society
- ItemA novel [18F]fluoride relay reagent for radiofluorination reactions(John Wiley & Sons, Inc, 2019-05-26) Zhang, B; Fraser, BH; Klenner, MA; Chen, Z; Liang, SH; Massi, M; Robinson, AJ; Pascali, GObjectives Fluorine‐18 is the most utilized radioisotope in Positron Emission Tomography (PET), but the wide application of fluorine‐18 radiopharmaceuticals is hindered by its challenging labelling conditions. This necessitates production at centralized PET centres with highly specialized equipment including cyclotrons, hot cells, synthesizers, and HPLC capabilities, which ultimately limit the availability of fluorine‐18 tracers to those whose production has a large marketing scale (e.g., [18F]FDG). As such, many potentially important leads remain underutilized. Herein, we describe the use of [18F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres (Figure 1). Methods [18F]ESF was produced from 2,4,6‐trichlorophenylethenesulfonate using a microfluidic system and was stored on inert cartridges. The cartridges could be shipped remotely where trapped [18F]ESF was liberated by chosen solvent to a vial containing precursor and additives. The reaction mixture was then stirred and heated using a heating block. Reaction conditions including temperature, time, precursor concentration, and additives were optimised, and the radiochemical yields (RCYs) were compared with those for traditional [18F]fluoride method. Results We found that conditions of 1 mg/mL precursor, 0.5 mg/mL tetraethylammonium bicarbonate as additive, temperature of 100°C, and time of 15 min were useful to assess radiofluorination scope on commercially available precursors. The obtained RCYs were compared with those generated from traditional dried [18F]fluoride source and no statically significant difference was observed for most precursors. Some differences on RCYs, both positive and negative, were noted when novel type of precursors (i.e., boronic acids, iodonium ylides) were tested. Conclusions We have developed a method to perform radiofluorinations using a new radiofluoride relay reagent, [18F] ESF. Such method reduces the reaction equipment needed, in the simplest case to a simple heating block, single‐use vials and magnetic stir bar. Notably, this new process is not only compatible with typical commercial precursors, but also feasible to accommodate emerging precursors with novel leaving groups. © 2019 The Authors
- ItemRhenium complexation‐dissociation strategy for fluorine‐18 labelling of bidentate PET ligands(John Wiley & Sons, Inc, 2019-05-26) Klenner, MA; Pascali, G; Zhang, B; Massi, M; Fraser, BHObjectives Pursuant to the discovery that rhenium complexation promotes fluorine‐18 radiolabelling of 1,10‐phenanthroline systems under low temperature, quasi‐aqueous conditions, which circumvent the need for azeotropic drying, we expanded our investigation towards thermal decomplexation strategies to improve the radiosynthesis of similar pyridinyl bidentate tracers. Methods Thirty‐eight compounds were synthesised based upon chloro, bromo, nitro, and fluoro substitutions of 1,10‐ phenanthroline, 2,2’‐bipyridine and 8‐hydroxyquinoline structures and their respective rhenium tricarbonyl chloride complexes. Each of these compounds, save for the nonradioactive fluoro substituted standards, were reacted (>n = 8) under microfluidic conditions with tetraethyl ammonium [18F]fluoride in anhydrous DMSO solvent with increasing reaction temperatures ranging from 50°C to 190°C in 20°C increments. All other parameters such as the precursor quantity, radioactivity, and flow rate/reaction time were kept constant (0.08 μmol, 29 ± 10 MBq, 20 μL·min−1/47 s, respectively). Radiochemical yields (RCYs) for each reaction were then calculated from the Radio‐HPLC peak integrations of the non‐isolated products. Results High RCYs were observed for the [18F]fluoride substitution of rhenium complexed 1,10‐phenanthroline structures (up to 91%) at temperatures ≤90°C, which could prove useful as a novel method for producing PET‐optical tracers given the optical emission properties of rhenium. Good RCYs were also observed for the 2,2’‐bipyridine rhenium complexes, peaking at 84% at 130°C in one example, which then dissociated to form the radiolabelled ligand in 82% RCY at a higher temperature of 190°C, as shown in Figure 1. Radiolabelling of these ligands was unsuccessful under conventional conditions using dry [18F]fluoride, thus establishing rhenium complexation‐dissociation as a novel method for radiolabelling. The fluorine‐18 labelling of 8‐ hydroxyquinoline structures was also tested as a means of improving the radiosynthesis of Alzheimer's disease imaging PET tracers such as [18F]CABS13. While preliminary rhenium complexation‐dissociation experiments have not yet improved on the radiosynthesis of [18F]CABS13 (5% RCY of ligand & 18% RCY of rhenium complex vs 19±5% RCY of ligand in literature), such experiments have enabled the radiosynthesis of related structures, which could not be radiolabelled under conventional conditions using dry [18F]fluoride (eg, [18F]5‐ fluoro‐8‐hydroxyquinoline). Conclusions We report a novel radiofluorination method utilising the rhenium complexation of pyridinyl bidentate structures. This method facilitates radiolabelling of certain analogues of 2,2’‐bipyridine and 8‐hydroxyquinoline structures, which do not radiolabel under conventional conditions. Investigations into monopyridine structures and the development of milder methods of decomplexation are currently ongoing. © 2019 The Authors
- ItemRhenium(i) complexation–dissociation strategy for synthesising fluorine-18 labelled pyridine bidentate radiotracers(Royal Society of Chemistry, 2020-02-28) Klenner, MA; Zhang, B; Ciancaleoni, G; Howard, JK; Maynard-Casely, HE; Clegg, JK; Massi, M; Fraser, BH; Pascali, GA novel fluorine-18 method employing rhenium(I) mediation is described herein. The method was found to afford moderate to high radiochemical yields of labelled rhenium(I) complexes. Subsequent thermal dissociation of the complexes enabled the radiosynthesis of fluorine-18 labelled pyridine bidentate structures which could not be radiofluorinated hitherto. This rhenium(I) complexation–dissociation strategy was further applied to the radiosynthesis of [18F]CABS13, an Alzheimer's disease imaging agent, alongside other 2,2′-bipyridine, 1,10-phenanthroline and 8-hydroxyquinoline labelled radiotracers. Computational modelling of the reaction mechanism suggests that the efficiency of rhenium(I) activation may be attributed to both an electron withdrawal effect by the metal center and the formation of an acyl fluoride intermediate which anchors the fluoride subsequent to nucleophilic addition. © The Royal Society of Chemistry 2020 - Open Access
- ItemSynthesis, bioconjugation and stability studies of [18F]ethenesulfonyl fluoride(John Wiley & Sons, Inc, 2018-06-20) Zhang, B; Pascali, G; Wyatt, NA; Matesic, L; Klenner, MA; Sia, TR; Guastella, AJ; Massi, M; Robinson, AJ; Fraser, BHFluorine-18 labelled prosthetic groups (PGs) are often necessary for radiolabelling sensitive biological molecules such as peptides and proteins. Several shortcomings, however, often diminish the final yield of radiotracer. In an attempt to provide higher yielding and operationally efficient tools for radiolabelling biological molecules, we describe herein the first radiochemical synthesis of [18F]ethenesulfonyl fluoride ([18F]ESF) and its Michael conjugation with amino acids and proteins. The synthesis of [18F]ESF was optimised using a microfluidic reactor under both carrier-added (c.a.) and no-carrier-added (n.c.a.) conditions, affording, in a straightforward procedure, 30-50% radiochemical yield (RCY) for c.a. [18F]ESF and 60-70% RCY for n.c.a. [18F]ESF. The conjugation reactions were performed at room temperature using 10 mg/mL precursor in aqueous/organic solvent mixtures for 15 min. The radiochemical stability of the final conjugates was evaluated in injectable formulation and rat serum, and resulted strongly substrate dependent and generally poor in rat serum. Therefore, in this work we have optimised a straightforward synthesis of [18F]ESF and its Michael conjugation with model compounds, without requiring chromatographic purification. However, given the general low stability of the final products, further studies will be required for improving conjugate stability, before assessing the use of this PG for PET imaging. © 2018 John Wiley & Sons, Inc.
- ItemSynthesis, structure and conformational mobility of tetra-substituted cyanomethoxy p-tert-butylcalix[4]arenes(Royal Society of Chemistry, 2016-04-04) D'Alessio, D; Krause-Heuer, AM; Skelton, BW; Fraser, BH; Massi, M; Ogden, MIThe syntheses and single crystal X-ray structure determinations of 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetrakis(cyanomethoxy)calix[4]arene (partial-cone conformer), 5,11,17,23-tetra-tert-butyl-25,27-bis(diethylcarbamoylmethoxy)-26,28-bis(cyanomethoxy)calix[4]arene (cone and partial-cone conformers), 5,11,17,23-tetra-tert-butyl-25,26,27-tris(cyanomethoxy)-28-hydroxycalix[4]arene, and 5,11,17,23-tetra-tert-butyl-25-diethylcarbamoylmethoxy-26,27,28-tris(cyanomethoxy)calix[4]arene (cone conformer) are reported. The calixarenes are found to be conformationally mobile when heated in DMSO, favouring the partial-cone conformer at equilibrium. The tris-substituted cyanomethoxy derivative was found to assume the partial-cone conformation in the solid state. Attempts to convert nitrile groups to tetrazole moieties in derivatives containing both amide and nitrile groups were unsuccessful. © The Authors - CC-BY licence
- ItemTelescoping the synthesis of the [18F]CABS13 Alzheimer's disease radiopharmaceutical via flow microfluidic rhenium(I) complexations(John Wiley & Sons, Inc, 2020-09-24) Klenner, MA; Fraser, BH; Moon, V; Evans, BJ; Massi, M; Pascali, GThe syntheses of rhenium(I) complexes were achieved under flow microfluidic conditions. The use of a single microreactor was applied towards complexation of the 6-chloro-2,2'-bipyridine diimine ligand, with ideal complexation conditions around 170 °C. Subsequent radiolabelling with [18F]fluoride was further achieved by flowing through a second heated microreactor, alongside a stream of dried radiofluorination media. Temperature modulation across both microreactors resulted in 23.6 % and 37.0 % radiochemical yield (RCY) of [18F]6-fluoro-2,2'-bipyridine and its associated [18F]tricarbonyl(2-fluoro-2,2'-bipyridine)rhenium(I) chloride complex, respectively. Translation of this set-up to the synthesis of the [18F]CABS13 Alzheimer's disease positron emission tomography (PET) imaging agent was achieved with the incorporation of a third microreactor to enable thermal control of the complexation, fluorination and decomplexation pathways. Optimal RCYs of 2.7 % and 1.9 % of [18F]CABS13 and its rhenium(I) complexation were achieved in-flow, respectively. However, discrepancies in the RCYs were found to arise from differences in the grade of anhydrous dimethyl sulfoxide (DMSO) employed in the continuous-flow reactions. Anhydrous DMSO from Sigma-Aldrich (≤ 99.9 %) in former experiments afforded higher yielders in comparison to replicate experiments employing anhydrous DMSO from Merck Millipore (≤ 99.7 %), thus demonstrating that control of the solvent grade is key to optimizing reaction RCYs. © 2020 Wiley-VCH GmbH