Browsing by Author "Perkins, G"

Now showing 1 - 7 of 7
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    Microfluidic implementation of Ru-catalyzed methylation of amines using CO2 as carbon source
    (Akadémiai Kiadó Zrt, 2016-06-22) Perkins, G; Khatib, O; Peterson, MB; Kallinen, A; Pham, TQ; Ung, AT; Greguric, I; Pascali, G
    Carbon dioxide chemistry is an area of continuing growth in recent times, due to socioeconomic and environmental reasons. Several methods have now been reported for obtaining N-methylation on primary and secondary amines directly from CO2. We have translated in two microfluidic setups (Slug Flow [SF] and Tube-in-Tube [TiT]) a ruthenium (Ru)-catalyzed process previously reported using a pressure vessel. Here, we demonstrate how the SF approach is more efficient but requires more input to reach a steady state, while the TiT system is less efficient but more tuneable.We have tested these processes on three model amines and two radiopharmaceutical precursors that are routinely used in 11C chemistry. The microfluidic processes tested are also potentially more efficient than the pressure vessel counterpart, in terms of amount of Ru catalyst needed (1% vs. 10%) and projected reaction completion time. © 2016 Akadémiai Kiadó Zrt.
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    Multiple patient batch production of 195mPt cisplatin and 195mPt carboplatin for use in drug risk assessment and optimisation of patient dose
    (Elsevier Science, 2010-08-01) Perkins, G; Smith, SV
    Platinum chemotherapeutics are used extensively as a first line treatment in over 28% of all cancers and widely as a second line treatment in combination with biological markers such as Herceptin. Over 20% of patients will experience maximum tolerate dose and significant side effects because dosage is often estimated using unreliable and indirect methods such as surface area and glomerular filtration rates. We are interested in providing a molecular imaging tool that allows the physician to screen a patient, monitor response and drug resistance and to personalise treatment regimes in order to reduce side effects. The ability to produce platinum radiopharmaceuticals commercially has been limited by long and unreliable synthetic processes. We have developed patent technology for the production of reactor base platinum radiopharmaceuticals, such as 195mPt-cisplatin and 195mPt-carboplatin. This study reports the neutron activation of 194platinum target material in the new research reactor OPAL and validation of the production of multiple (five) patient batches for both 195mcisplatin and 195mcarbplatin. Yields were 53±3% and 29±4%, respectively, with specific activities of up to 8MBq/mg. Production times were dramatically reduced from up to 24 h to less than 3 h using the new process.© 2010, Elsevier Ltd.
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    NEMA NU 4-2008 validation and applications of the PET-SORTEO Monte Carlo simulations platform for the geometry of the Inveon PET preclinical scanner
    (IOP Publishing, 2013-09-10) Boisson, F; Wimberley, CA; Lehnert, W; Zahra, D; Pham, TQ; Perkins, G; Hamze, H; Grégoire, MC; Reilhac, A
    Monte Carlo-based simulation of positron emission tomography (PET) data plays a key role in the design and optimization of data correction and processing methods. Our first aim was to adapt and configure the PET-SORTEO Monte Carlo simulation program for the geometry of the widely distributed Inveon PET preclinical scanner manufactured by Siemens Preclinical Solutions. The validation was carried out against actual measurements performed on the Inveon PET scanner at the Australian Nuclear Science and Technology Organisation in Australia and at the Brain and Mind Research Institute and by strictly following the NEMA NU 4-2008 standard. The comparison of simulated and experimental performance measurements included spatial resolution, sensitivity, scatter fraction and count rates, image quality and Derenzo phantom studies. Results showed that PET-SORTEO reliably reproduces the performances of this Inveon preclinical system. In addition, imaging studies showed that the PET-SORTEO simulation program provides raw data for the Inveon scanner that can be fully corrected and reconstructed using the same programs as for the actual data. All correction techniques (attenuation, scatter, randoms, dead-time, and normalization) can be applied on the simulated data leading to fully quantitative reconstructed images. In the second part of the study, we demonstrated its ability to generate fast and realistic biological studies. PET-SORTEO is a workable and reliable tool that can be used, in a classical way, to validate and/or optimize a single PET data processing step such as a reconstruction method. However, we demonstrated that by combining a realistic simulated biological study ([11C]Raclopride here) involving different condition groups, simulation allows one also to assess and optimize the data correction, reconstruction and data processing line flow as a whole, specifically for each biological study, which is our ultimate intent. © 2017 IOP Publishing
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    Optimisation of [11C]raclopride production using a synthra GPextent system
    (Bentham Science Publishers, 2014-12-01) Perkins, G; Sheth, R; Greguric, I; Pascali, G
    The dopamine D2 receptor radiotracer [(11)C]Raclopride is used extensively in clinical and preclinical imaging. Currently, a wide range of methods to produce [(11)C]Raclopride have been developed using traditional vessel reactions as well as cartridge or captive solvent. This work reports the optimisation of the production of [(11)C]Raclopride using a Synthra GPextent, comparing various methods. With optimised conditions, we were able to obtain 4±2% (ndc) yield of [(11)C]Raclopride (100 GBq [(11)C]CO2, n = 42) in 25 min. The radiochemical purity was >95% with specific activities of 135±41 MBq/nmol at end of synthesis. © 2014 Bentham Science Publishers
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    Production of high specific activity Pt-195m-cisplatinum at South African Nuclear Energy Corporation for phase 0 clinical trials in healthy individual subjects
    (Wiley, 2013-07-23) Zeevaart, JR; Wagener, J; Marjanovic-Painter, B; Sathekge, M; Soni, N; Zinn, C; Perkins, G; Smith, SV
    Platinum agents continue to be the main chemotherapeutic agents used in the first-line and second-line treatments of cancer patients. It is important to fully understand the biological profile of these compounds in order to optimize the dose given to each patient. In a joint project with the Australian Nuclear Science and Technology Organisation and the Nuclear Medicine Department at Steve Biko Academic Hospital, South African Nuclear Energy Corporation synthesized and supplied (195m) Pt-cisplatinum (commonly referred to as cisplatin) for a clinical pilot study on healthy volunteers. Enriched (194) PtCl2 was prepared by digestion of enriched (194) Pt metal (>95%) followed by thermal decomposition over a 3 h period. The (194) PtCl2 was then placed in a quartz ampoule, was irradiated in SAFARI-1 up to 200 h, then decay cooled for a minimum of 34 h prior to synthesis of final product. (195m) Pt(NH3 )2 I2 , formed with the addition of KI and NH4 OH, was converted to the diaqua species [(195m) Pt(NH3 )2 (H2 O)2 ](2+) by reaction with AgNO3 . The conversion to (195m) Pt-cisplatinum was completed by the addition of concentrated HCl. The final product yield was 51.7% ± 5.2% (n = 5). The chemical and radionuclidic purity in each case was >95%. The use of a high flux reactor position affords a higher specific activity product (15.9 ± 2.5 MBq/mg at end of synthesis) than previously found (5 MBq/mg). Volunteers received between 108 and 126 MBq of radioactivity, which is equivalent to 6.8-10.0 mg of carrier cisplatinum. Such high specific activities afforded a significant reduction (~50%) in the chemical dose of a carrier cisplatinum, which represents less than 10% of a typical chemotherapeutic dose given to patients. A good manufacturing practice GMP compliant product was produced and was administered to 10 healthy volunteers as part of an ethically approved Phase 0 clinical trial. The majority of the injected activity 27.5% ± 5.8% was excreted in the urine within 5 h post injection (p.i.). Only 8.5% ± 3.1% of cisplatinum remained in blood pools at 5 h, which gradually cleared over the 6-day monitoring period p.i. At the end of the study (6 days p.i.), a total of 37.4% ± 5.3% of the product had cleared from the blood into urine, and approximately 63% remained in the body. The significantly lower concentration of carrier cisplatinum used for imaging resulted in a well-tolerated product. © 2013 John Wiley & Sons, Ltd.
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    Quantification of dopamine d2 receptor density and apparent affinity can be used to longitudinally assess transient striatal variations during adolescence using [11c]raclopride pet imaging
    (John Wiley & Sons, Inc., 2017-04-11) Callaghan, PD; Sobbi, PF; Safavi-Naeini, M; Wimberley, CA; Davis, E; Zahra, D; Arthur, A; Rahardjo, GL; Perkins, G; Pascali, G; Reilhac-Laborde, A; Grégoire, MC
    Background Transient increases in striatal dopamine D2 receptors occur during adolescence in rats, correlating with a developmental epoch where synaptic pruning occurs. Alteration of these processes with external stresses during adolescence may lead to affective disorders later in life. Longitudinal PET imaging with [11C]raclopride using a partial saturation design allows assessment of density (Bavail) and affinity changes (appKd) to map neurodevelopmental changes in D2 expression, which necessitates a significant level of receptors occupancy during the PET study. Aims Validate that repeated transient partial saturation of D2 receptors does not bias measures of D2 Bavail and appKd assessed using PET/CT imaging with [11C]raclopride. Methods Three cohorts of male Sprague-Dawley rats (n=6-7/group) underwent a single session of PET/CT imaging (INVEON, Siemens, USA) with [11C]raclopride (5 nmol injected i.v.) as naïve or after repeated partial saturation of D2 receptors: Cohort A received 5nmol raclopride (i.v) weekly from PND35 (postnatal day) to PND96 with PET imaging session at PND96, cohort B was scanned at PND96; Cohort C was scanned at PND35 Datasets were reconstructed (2D-FBP), coregistered with CT and time-activity data extracted using age matched atlas-based volumes of interest (striatum, cerebellum). in vivo receptor density and appKd were derived using kinetic modelling (comparisons used 1-way ANOVA follow by post hoc test). Results Expected differences in Bavail and appKd were seen between the adolescent (PND35) and the adult (PND96) cohorts, corresponding with increases in D2 receptor consistently reported in the literature using post mortem methods. No significant difference was observed in both Bavail and appKd in cohort A, exposed to repeated D2 partial saturation, compared to the naïve cohort B. Conclusion Longitudinal quantification of dopamine D2 receptor density and apparent affinity in vivo using [11C]raclopride PET imaging with partial saturation can be used to map changes in adolescent and adult rats.
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    Test-retest reliability and inter scanner variability of 11C-raclopride striatal binding potentials between two INVEON PET/CT imaging systems for naïve Sprague Dawley rats
    (Wiley, 2014-04-16) Callaghan, PD; Zahra, D; Wimberley, CA; Arthur, A; Rahardjo, GL; Hamze, H; Davis, E; Nguyen, A; Boisson, F; Perkins, G; Pascali, G; Reilhac, A; Grégoire, MC
    Background: 11C-raclopride is a routine tracer for quantification of dopamine D2 receptors in neurological and psychiatric disease. D2 imaging in key longitudinal models has significant utility of understanding mechanisms and therapeutic interventions. Aims: Optimisation of preclinical imaging and data analysis protocols for 11C-raclopride in rat brain. Methods: a) Test-retest reliability: Naïve male Sprague Dawley rats (n = 6) underwent test-retest assessment of binding potential variability, with two scans, 1 week apart. Rats were anaesthetised (1–5% isoflurane) and received 11C-raclopride (>0.1 nmol, 20–40 MBq) during 1 hour image acquisition (Siemens Inveon PET/CT), followed by a 10 minute CT scan. b) Assessment of the intersystem variability of the INVEON scanners (n = 12). Test-retest experiments were performed on a second INVEON system. c) Assessment of inter system variability with arterial blood sampling (n = 5). Acquisitions were performed (as above) with prior femoral artery cannulation: 23 blood samples (∼30 ul) were collected during PET acquisition, and plasma metabolite corrected input functions generated. PET list mode data were histogrammed (23 frames) and reconstructed with 2D filtered backprojection algorithm. The impact of some post-reconstruction image processing techniques, such iterative deconvolution of the image and data denoising techniques, onto the accuracy and reliability of the computed parameter of interest were also investigated. Binding potential parametric maps were calculated from the dynamic PET data (using either a standard reference tissue modelling using the cerebellum TAC (test-retest), and or a 2 compartment kinetic modelling with input function). Preliminary results: Significant improvements were seen for tissue activity data after denoising /iterative deconvolution (see figure). Analysis of binding potential data are currently in progress. Conclusion: Assessment of within and intersystem variability will aid the appropriate statistical design of future longitudinal 11C-raclopride imaging studies. Improvements from post-reconstruction image processing techniques show significant benefits. © 1999-2022 John Wiley & Sons, Inc.