Browsing by Author "Burgess, L"

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    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
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    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
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    Prenatal poly I:C age-dependently alters cannabinoid type 1 receptors in offspring: a longitudinal small animal PET study using [18F]MK-9470
    (Elsevier, 2014-05-10) Verdurand, M; Dalton, VS; Nguyen, VH; Grégoire, MC; Zahra, D; Wyatt, NA; Burgess, L; Greguric, I; Zavitsanou, K
    Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [18F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic–polyribocytidilic acid (poly I:C) (4 mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32–42 (adolescence) and in the same animals again at PNDs 75–79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p = 0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p = 0.034) and hypothalamus (p = 0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies. © Elsevier