In vitro and in vivo comparison of the novel

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In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

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Conference Abstract: DFO-cyclo versus DFO

In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


ESRR 18, 19th European Symposium on Radiopharmacy and Radiopharmaceuticals, 05-08 April 2018, Groningen, Netherlands

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation of 89Zr in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: DFO-CYCLO VERSUS DFO
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Gadoxetate relaxivities increase significantly after hepatic

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Gadoxetate relaxivities increase significantly after hepatic uptake at clinical field strength impacting kinetic modelling for liver function analysis (Conference Abstract)

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Conference Abstract: Gadoxetate relaxivity in liver

Gadoxetate relaxivities increase significantly after hepatic uptake at clinical field strength impacting kinetic modelling for liver function analysis (Conference Abstract)

Gregor Jost, Gunnar Schuetz, Hubertus Pietsch


ISMRM Annual Meeting 2018, 16-21 June 2018,Paris, France

 

Abstract

Gadoxetate has been clinically approved for detection and characterization of focal liver lesions by MRI. It exhibits moderate protein binding and is excreted from the body partially through the kidneys and partially by a hepatobiliary pathway. Hepatocytes take up gadoxetate mainly via OAPT and NTCP transporters and excrete it into the bile mainly utilizing Mrp2. By means of dynamic acquisition of gadoxetate signal intensity during liver uptake and excretion followed by application of a suitable kinetic model, the activity of the aforementioned liver transporters can be estimated. For kinetic modelling the gadoxetate concentration for each time point is needed which can be calculated from the signal intensity if r1 in tissue is known. In 1992 Schuhmann-Giampieri et al. reported r1 of gadoxetate to be significantly higher in liver tissue compared to blood at 0.47T. This effect has been attributed to gadoxetate’s protein binding which leads to an increased rotational correlation time. Gadoxetate relaxivities at 1.5T, 3T and 4.7T have since then been reported for water and plasma, but not for hepatocytes. We here present relaxivities for gadoxetate in hepatocytes at 1.5T and 3T to complement the original Schuhmann-Giampieri data. Measurements at 7T are in progress. Interestingly, r1 of gadoxetate after uptake into hepatocytes is about 2x higher compared to plasma and does not decrease with increasing field strength as has been shown for high relaxivity Gd based contrast agents exhibiting high protein binding e.g. gadofosveset. Gadoxetate’s higher r1 in hepatocytes has to be taken into account for pharmacokinetic modelling of dynamic gadoxetate MRI at clinical field strength, which has not been done so far.

CONFERENCE ABSTRACT: GADOXETATE RELAXIVITY IN LIVER
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Overview of the TRanslational Imaging in Drug SafeTy

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Overview of the TRanslational Imaging in Drug SafeTy AssessmeNt (TRISTAN) IMI Consortium and Progress towards Standardization of MR Biomarkers of Liver Injury and Drug-Drug Interactions (Conference Abstract)

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Conference Abstract: DILI imaging biomarkers

Overview of the TRanslational Imaging in Drug SafeTy AssessmeNt (TRISTAN) IMI Consortium and Progress towards Standardization of MR Biomarkers of Liver Injury and Drug-Drug Interactions (Conference Abstract)

Aleksandra Galetin, Claudia Green, Catherine Hines, Paul Hockings, Lisa Jarl, Gerry Kenna, Sascha Koehler, Iina Laitinen, Xiangjun Meng, Corin Miller, Kayode Ogungbenro, Geoff Parker, Ian Rowe, Gunnar Schuetz, Daniel Scotcher, Steven Sourbron, Klaus Strobel, Sirisha Tadimalla, Ekaterina Tankisheva, John Waterton, Sabina Ziemian


In Vivo MR Gordon Research Conference, 15-20 July 2018, Andover, NH, USA

 

Abstract

In 2017, the TRanslational Imaging in Drug SafeTy AssesmeNt (TRISTAN) Innovative Medicines Initiative (IMI) consortium commenced to leverage the potential of imaging techniques to improve drug safety analysis and translatability of findings by validating and making available imaging procedures as assays to provide biomarkers for widespread use. As such, hepatobiliary transporter assessment is being undertaken using gadoxetate-enhanced MRI-derived biomarkers. Gadoxetate is known to be a substrate for the human influx transporters OATP1B1, OATP1B3, and NTCP, and the efflux transporters MRP2 and MRP3, and their rat orthologues. These transporters contribute to relevant transporter-mediated drug-drug interactions and mediate hepatobiliary clearance of numerous drugs which cause drug-induced liver injury. In addition, inhibition of bile acid excretion by drugs is an important mechanism by which drug-induced liver injury can be initiated. In view of this, the authors seek to validate influx and efflux rates of gadoxetate as an imaging biomarker assay for in vivo liver transporter assessment.

CONFERENCE ABSTRACT: DILI IMAGING BIOMARKERS
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Systematic review: In vivo imaging in animal models

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Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

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Conference Abstract: DIILD Animal Models

Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Karin von Wachenfeldt, Kashmira Pindoria, Michael Haase, Simon Campbell, Juan X. Delgado, Mark Wright, John C. Waterton and Lars E. Olsson - on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 September 2018, Paris, France

 

Abstract

Translational Imaging Biomarkers (IB) are needed to avoid or manage drug-toxicity, resulting in drug-induced interstitial lung disease (DIILD). We reviewed the literature on in vivo imaging to detect and assess lung lesions in animal models with relevance to DIILD and with pathological changes resembling clinical DIILD.

CONFERENCE ABSTRACT: DIILD ANIMAL MODELS
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Imaging biomarkers of oedema and fibrosis in a rat

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Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

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Conference Abstract: Imaging of DIILD in rats

Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Anders Örbom, Per-Ola Önnervik, Karin von Wachenfeldt and Lars E. Olsson- on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 Septembr 2018, Paris, France

 

Background

Drugs used to treat various diseases may induce lung injury known as drug induced interstitial lung disease (DIILD). Clinical and pre-clinical studies within the TRISTAN-consortium are aimed at finding translational Imaging Biomarkers (IB) that can indicate progression of DIILD at an early stage. In the present in vivo study, magnetic resonance imaging (MRI) was applied along with analyses of lavage and lung tissue.

CONFERENCE ABSTRACT: IMAGING OF DIILD IN RATS
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Slow infusion improves precision of liver function

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Slow infusion improves precision of liver function measurements by DCE-MRI (Conference Abstract)

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Conference Abstract: Slow infusion dce-mri

Slow infusion improves precision of liver function measurements by DCE-MRI (Conference Abstract)

Sirisha Tadimalla and Steven Sourbron


The British Chapter of ISMRM Annual Meeting, 24-26 September 2018, Somerville College, Oxford

 

Background

Quantitative dynamic contrast-enhanced (DCE) MRI with a rapidly injected bolus of gadoxetate can be used to quantify liver perfusion and transporter function [1,2]. Measuring these rapid changes requires high temporal resolution, and this involves compromises in spatial resolution, coverage or SNR. However, when the aim is to measure hepatocellular function (a slow process), rather than perfusion (a fast process), there is no rationale for a rapid injection.

CONFERENCE ABSTRACT: SLOW INFUSION DCE-MRI
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Accuracy, repeatability, and reproducibility of R1

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Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

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Conference Abstract: Phantom R1 Repeabililty

Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

JC Waterton, CDG Hines, PD Hockings, I Laitinen, S Ziemian, S Campbell, M Gottschalk, C Green, M Haase, K Hoffmann, H-P Juretschke, S Koehler, W Lloyd, Y Luo, I Mahmutovic Persson, JPB O Connor, LE Olsson, GJM Parker, K Pindoriah, JE Schneider, D Steinmann, K Strobel, I Teh, A Veltien, X Zhang, G Schuetz


British Chapter ISMRM Annual Meeting 24th-26th September 2018, Oxford, UK Poster Abstract PO-19


Background:  Many translational MR biomarkers derive from measurements of the longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking.  Objective: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. Methods: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days.  R1 was analysed in three different regions of interest, giving 360 measurements in total.  Root-mean-square repeatability and reproducibility coefficients of variation were calculated.  Relaxivities were calculated.  Results: Day-to-day repeatability (N=180 regions of interest) was 2.3%.  Between-centre reproducibility (N=9 centres) was 1.4%.  The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1mM-1 at 3T and 0.94 s-1mM-1 at 11.7T.

CONFERENCE ABSTRACT: PHANTOM R1 REPEABILILTY
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In vitro and in vivo evaluation of novel 89Zr-chelators

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In vitro and in vivo evaluation of novel 89Zr-chelators (Conference Abstract)

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Conference Abstract: 89Zr chelate evaluation

In vitro and in vivo evaluation of novel 89Zr-chelators (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Adrien Dubois, Laurene Da Costa, Victor Goncalves, Franck Denat


Third international edition of the symposium on Technetium and Other Radiometals in Chemistry and Medicine (TERACHEM 2018), September 26-29, 2018, Bressanone (BZ), Italy

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO).1 Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation in mineral bone. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for more stable 89Zr chelators.

CONFERENCE ABSTRACT: 89ZR CHELATE EVALUATION
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Development and evaluation of a new Interleukin

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Development and evaluation of a new Interleukin-2 PET radioligand Al[18F]RESCA-IL2: comparison with [18F]FB-IL2 (Conference Abstract)

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Conference Abstract: IL-2 PET

Development and evaluation of a new Interleukin-2 PET radioligand Al[18F]RESCA-IL2: comparison with [18F]FB-IL2 (Conference Abstract)

I.F. Antunes, E.L. van der Veen, E.E.M. Deneer, F. Cleeren, G. Bormans, P.H Elsinga, R.A.J.O. Dierckx, E.G.E de Vries, E.F.J. de Vries


31st Annual Congress of the European Association of Nuclear Medicine, 13-17 October 2018, Düsseldorf

 

Aim

Interleukin-2 is a 15.5 kDa glycoprotein that binds with high affinity to IL2 receptors (IL2R) that are overexpressed on activated T-cells, which are involved in various pathological diseases, such as autoimmune diseases, but also play a major role in the tumor immune response. We have developed 18F-FB-IL2 which has been successfully used for detecting activated T-cells in rodents [1]. Recently, a GMP-compliant production of 18F-FB-IL2 for clinical use was implemented, but the production method proved to be complex and time-consuming. Therefore, we now developed a simplified method to label IL2 with 18F. Here we present the synthesis of Al 18F-RESCA-IL2 and its comparison to 18F-FB-IL2.

CONFERENCE ABSTRACT: IL-2 PET
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Evaluation of the in vitro and in vivo characteristics

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Evaluation of the in vitro and in vivo characteristics of the novel89Zr-octacoordinated chelator DFO-cyclo* compared to the hexacoordinated DFO (Conference Abstract)

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Conference Abstract: Novel 89Zr chelator

Evaluation of the in vitro and in vivo characteristics of the novel89Zr-octacoordinated chelator DFO-cyclo* compared to the hexacoordinated DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


31st Annual Congress of the European Association of Nuclear Medicine, 13-17 October 2018, Duesseldorf

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zrr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: NOVEL 89ZR CHELATOR
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