ANSTO :: Browsing by Author "Lengkeek, NA"

Browsing by Author "Lengkeek, NA"

Now showing 1 - 13 of 13

Developing national capability for the production and use of radiometal based radiopharmaceuticals
(John Wiley & Sons, Inc, 2013-04-11) Lengkeek, NA; Pellegrini, PA; Oehlke, E; Fraser, BH; Greguric, I
Radiometals remain key radioisotopes for radio-medicine; the mainstay diagnostic medical imaging isotope, 99mTc, and important radioisotopes for radiotherapy, 90Y and 153Sm. However, the worldwide growth in PET centres, driven by the wildly successful [18F]-FDG, has provided a yet to be seized opportunity to deliver radiometal-based radiopharmaceuticals with clinical relevance to researchers. An ever growing set of radiometals is becoming available in Australia covering a wide range of half-lives, nuclear and chemical properties, these include 64Cu, 68Ga, 86Y, 89Zr, and looking into the near future, 44Sc, 45Ti and 90Nb. ANSTO's Lifesciences division is working to provide the Australian academic and clinical communities access to the following key areas. Radioisotope supply Two in-house 68Ge/68Ga generators; one solely for research and a larger generator for pre-clinical trials, provide access to this key radioisotope. ANSTO has provided financial and technical support to numerous cyclotron centres around Australia for development of solid targetry facilities, ensuring supply of 124I, 64Cu, 86Y and 89Zr in the short-term and 44Sc, 45Ti and 90Nb later. In coming years the OPAL reactor will begin producing pharmaceutical grade 177Lu as part of the Australian government's investment in nuclear medicine. Radiometal Labelling Research and Development In addition to our programs developing new ligands, tracers and improved radiometal labelling procedures, Lifesciences is supporting the development of new biomolecule treatments by providing researchers access to laboratories, procedures and expertise tailored specifically for functionalising biomolecules for radiometal labelling. Preclinical Radiometal Tracer Development We are working to deliver novel radiometal-based diagnostic tracers to the Australian research and clinical community by accessing the pre-clinical programs of our key international partnerships at Memorial Sloan Kettering Cancer Centre and Massachusetts General Hospital. Our initial objective is to supply the antibodies, i.e. [ 89 Zr]-J591. As our supply radiometals is diversified we will expand into proteins, peptides and other biomolecules. © 2013 John Wiley & Sons, Inc.
Development of novel ligands for emerging radiometal isotopes
(John Wiley & Sons, Inc., 2013-04-11) Ashford, ME; Burgess, L; Cheah, WC; Krause-Heuer, AM; Fraser, BH; Greguric, I; Lengkeek, NA
Background: The use of radiometals (non-Tc, non-Re) in targeted diagnosis and radiotherapy of different disease states has increased significantly over the last 15 years. ANSTO LifeSciences radiometals program seeks to provide a suite of radiometal tools for use in PET imaging and therapeutic modalities to improve upon the existing technologies which are currently dominated by 99mTc. This will enable researchers and clinicians to study and diagnose diseases with a greater efficacy and efficiency. Method: Many of the ligands currently available for radiometals have numerous drawbacks , including unfavourable in vivo properties such as thermodynamic and kinetic stability and poor lipophilicity. We are developing new ligand systems to have improved radiometal specificity while including design flexibility allowing us to manipulate properties such as biodistribution patterns, excretion rates, pharmacokinetics, thermodynamics and in vivo stability. The synthesis should be straightforward and cost effective and have the potential for bioconjugation in the initial design. Complexation studies are performed in vitro to assess the ligands suitability. Results: We are developing ligand systems for 68Ga, 89Zr, 64Cu, 90Y and 177Lu. We have prepared a novel analogue of the ubiquitous ligand NOTA (Figure 1, b); our system replaces the biologically labile carboxylic acid with a corresponding, biologically inert isotere, a tetrazole. This manipulation should provide additional stability and increased complex lipophilicity. Our studies have shown that a tetrazole analogue of NOTA (Figure 1, b) forms stable cold-metal complexes with potential PET metals of interest such as Ga3+. Conclusion: ANSTO LifeSciences provides a complete synthetic ligand and metal complex program, complementing its broader Radiometals Program. The aim of which is to provide an array of clinically relevant ligands that can be used in multiple applications for specific metal radiopharmaceuticals for improved patient outcomes. © 2013 John Wiley & Sons
Influence of metal ions on the Ga-68-labeling of dotatate
(Elsevier, 2013-12-01) Oehlke, E; Le, VS; Lengkeek, NA; Pellegrini, PA; Jackson, TW; Greguric, I; Weiner, R
The influence of metal cations (Fe3+, Fe2+, In3+, Cu2+, Ca2+, Al3+, Co2+, Lu3+, Ni2+, Pb2+, Ti4+, Y3+, Yb3+, Zn2+, and Zr4+) on the radiolabeling yield of [68Ga(DOTATATE)] was evaluated. Our most important observation was that, within our experimental limit, the metal ion/ligand ratio plays a critical role on the influence of most metal ions. More in-depth studies, with Cu2+ and Fe3+, revealed that reaction temperature and concentration changes have little effect, but speciation changes with pH are crucial. Furthermore, we found that [68Ga(DOTATATE)] is stable in the presence of high concentrations of Fe3+, Zn2+ and Pb2+, but transmetalates with Cu2+ at 95 °C. © 2013, Elsevier Ltd.
Ionophoric 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, MI
The 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
Lanthanoid “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, MI
Large 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
A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis
(Royal Society of Chemistry, 2012-11-12) Krause-Heuer, AM; Howell, NR; Matesic, L; Dhand, G; Young, EL; Burgess, L; Jiang, CD; Lengkeek, NA; Fookes, CJR; Pham, TQ; Sobrio, F; Greguric, I; Fraser, BH
Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic halides allowed systematic variation of lipophilicity (logP 1.94–3.31) without decreasing inhibition potency (IC50). From this series the p-methoxybenzyl analogue was selected for initial ‘proof-of-concept’ [18F]-fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/deprotection strategy. © 2013 Royal Society of Chemistry
Solvent extraction of rare earth elements using phosphonic/phosphinic acid mixtures
(Elsevier B.V., 2015-10-01) Quinn, JE; Soldenhoff, KH; Stevens, GW; Lengkeek, NA
This work examines the extraction of rare earths (Ce, Pr, Nd, Sm, Tb, Dy, Ho, Er, Yb, Lu and Y) by 2-ethylhexyl phosphonic acid 2-ethylhexyl mono-ester (EHEHPA), Cyanex 272, Cyanex 572 and mixtures of EHEHPA and Cyanex 272, to determine whether the mixed extractants could be beneficial to industrial rare earth separations. Analysis of the effect of pH and extractant concentration on distribution ratios indicated that addition of the phosphinic acid to EHEHPA resulted in an antagonistic effect. The antagonistic effect was confirmed using the method of continuous variation, and is thought to be due to an association between the phosphinic and phosphonic acids which reduces the free dimer concentrations of each component. Examination of 31P{1H} NMR spectra showed that for the mixed extractant the extracted yttrium complex was predominantly composed of EHEHPA. However, some Cyanex 272 was also found to be associated with yttrium, which suggests the formation of a mixed yttrium–EHEHPA–Cyanex 272 complex. Separation factors for the mixed extractants were similar to those of EHEHPA, while the maximum loading for equimolar extractants was approximately halved. The results suggest potential savings resulting from a reduction in the stripping acid required for the mixed extractant relative to equimolar EHEHPA; however equipment size would likely increase due to lower overall metal loading. © 2015 Elsevier B.V.
The synthesis and fluorescence profile of novel thalidomide analogues
(Elsevier B.V., 2015-10-21) Kampmann, SS; Skelton, BW; Yeoh, GC; Abraham, LJ; Lengkeek, NA; Stubbs, KA; Heath, CH; Stewart, SG
Herein we describe the synthesis of various simple N-alkyl thalidomide derivatives in order to determine their fluorescence excitation and emission profile. Following this, a series of more complex fragments were attached through a Huisgen 1,3-dipolar cycloaddition providing a more diverse fluorescence profile. A thalidomide azide derivative was also found to be particularly reactive in a copper-free click reaction with two known cyclooctynes. © 2015 Elsevier Ltd.
Synthesis and in vivo biological evaluation of 68Ga labelled carbonic anhydrase IX targeting small molecules for positron emission tomography
(American Chemical Society, 2016-06-20) Sneddon, D; Niemans, R; Bauwens, M; Yaromina, A; van Kuijk, SJA; Lieuwes, NG; Biemans, R; Pooters, I; Pellegrini, PA; Lengkeek, NA; Greguric, I; Tonissen, KR; Supuran, CT; Lambin, P; Dubois, L; Poulsen, S
Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, [68Ga]-2, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing 68Ga for preclinical CA IX imaging are scarce, and this is one of the first effective 68Ga compounds reported for PET imaging of CA IX. © 2016 American Chemical Society
Synthesis and in vivo evaluation of [123I]melanin-targeted agents
(American Chemical Society, 2015-08-15) Roberts, MP; Nguyen, VH; Ashford, ME; Berghofer, PJ; Wyatt, NA; Krause-Heuer, AM; Pham, TQ; Taylor, SR; Hogan, L; Jiang, CD; Fraser, BH; Lengkeek, NA; Matesic, L; Grégoire, MC; Denoyer, D; Hicks, RJ; Katsifis, A; Greguric, I
This study reports the synthesis, [123I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [131I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60–90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [123I]4 (ICF01012). The most favorable compounds ([123I]20, [123I]23, [123I]41, and [123I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [123I]20 and [123I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [123I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [123I]41 and [123I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [123I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [131I] therapeutic evaluation. ©2015, American Chemical Society
Synthesis and radiolabelling of DOTA-linked glutamine analogues with 67,68Ga as markers for increased glutamine metabolism in tumour cells
(MDPI (Multidisciplinary Digital Publishing Institute), 2013-06-19) Pellegrini, PA; Howell, NR; Shepherd, R; Lengkeek, NA; Oehlke, E; Katsifis, A; Greguric, I
DOTA-linked glutamine analogues with a C6- alkyl and polyethyleneglycol (PEG) chain between the chelating group and the l-glutamine moiety were synthesised and labelled with 67,68Ga using established methods. High yields were achieved for the radiolabelling of the molecules with both radionuclides (>90%), although conversion of the commercially available 67Ga-citrate to the chloride species was a requirement for consistent high radiochemical yields. The generator produced 68Ga was in the [68Ga(OH)4]− form. The 67Ga complexes and the 67Ga complexes were demonstrated to be stable in PBS buffer for a week. Uptake studies were performed with longer lived 67Ga analogues against four tumour cell lines, as well as uptake inhibition studies against l-glutamine, and two known amino acid transporter inhibitors. Marginal uptake was exhibited in the PEG variant radio-complex, and inhibition studies indicate this uptake is via a non-targeted amino acid pathway. © 2013 by the authors
Synthesis and stability studies of Ga‐67 labeled phosphonium salts
(John Wiley and Sons, 2016-11-07) Kardashinsky, M; Lengkeek, NA; Rendina, LM
Delocalized lipophilic cations such as tri- and tetra-arylphosphonium are able to diffuse across the mitochondrial membrane, which allows them to selectively accumulate in cells with a high transmembrane potential (ΔΨm). The mitochondrial membrane potential of cancer cells and cardiomyocytes has been reported to be significantly higher than that of normal epithelial cells. This feature can be exploited for the selective accumulation of phosphonium derivatives for the purposes of molecular imaging using radionuclides. Four structurally related Ga(III)-phosphonium salts were synthesized and fully characterized and found to be modest in toxicity toward T98G human glioblastoma cells (IC50 > 4 mM). High-activity (100 MBq) analogs containing Ga-67 were also synthesized and their stabilities in phosphate-buffered saline and human serum were determined. © 2016 John Wiley & Sons, Ltd.
Tunable and noncytotoxic PET/SPECT-MRI multimodality imaging probes using colloidally stable ligand-free superparamagnetic iron oxide nanoparticles
(Dove Press Ltd, 2017-01-27) Pham, THN; Lengkeek, NA; Greguric, I; Kim, BJ; Pellegrini, PA; Bickley, SA; Tanudji, MR; Jones, SK; Hawkett, BS; Pham, BTT
Physiologically stable multimodality imaging probes for positron emission tomography/single-photon emission computed tomography (PET/SPECT)-magnetic resonance imaging (MRI) were synthesized using the superparamagnetic maghemite iron oxide (γ-Fe2O3) nanoparticles (SPIONs). The SPIONs were sterically stabilized with a finely tuned mixture of diblock copolymers with either methoxypolyethylene glycol (MPEG) or primary amine NH2 end groups. The radioisotope for PET or SPECT imaging was incorporated with the SPIONs at high temperature. 57Co2+ ions with a long half-life of 270.9 days were used as a model for the radiotracer to study the kinetics of radiolabeling, characterization, and the stability of the radiolabeled SPIONs. Radioactive 67Ga3+ and Cu2+-labeled SPIONs were also produced successfully using the optimized conditions from the 57Co2+-labeling process. No free radioisotopes were detected in the aqueous phase for the radiolabeled SPIONs 1 week after dispersion in phosphate-buffered saline (PBS). All labeled SPIONs were not only well dispersed and stable under physiological conditions but also noncytotoxic in vitro. The ability to design and produce physiologically stable radiolabeled magnetic nanoparticles with a finely controlled number of functionalizable end groups on the SPIONs enables the generation of a desirable and biologically compatible multimodality PET/SPECT-MRI agent on a single T2 contrast MRI probe. © 2017 Dove Press Ltd under Creative Commons v3.0, BY, NC.

Browsing by Author "Lengkeek, NA"

Results Per Page

Sort Options