Clinical Gd-EOB-DTPA MRI to detect the inhibition

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Clinical Gd-EOB-DTPA MRI to detect the inhibition of hepatocyte transporters (Conference Abstract)

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Conference Abstract: Gadoxetate MRI to see liver transporter inhibition

Clinical Gd-EOB-DTPA MRI to detect the inhibition of hepatocyte transporters (Conference Abstract)

Sirisha Tadimalla


Hepatocyte Transporter Network Meeting, September 2019. HTNM 2019 Presentation.

CONFERENCE ABSTRACT: GADOXETATE MRI TO SEE LIVER TRANSPORTER INHIBITION
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Biological- and imaging biomarkers of oedema and fibrosis

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

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IBs of oedema and fibrosis in rat DIILD

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

Irma Mahmutovic Persson, Hanna Falk Håkansson, Anders Örbom, Per-Ola Önnervik, Janne Persson, Karin Von Wachenfeldt, Lars E. Olsson.


European Respiratory Journal 2019 54: PA2417. doi: 10.1183/13993003.congress-2019.PA2417.

Abstract

A large number of systemically administered drugs have the potential to cause DIILD. We aim to characterize a model of DIILD in the rat and develop imaging biomarkers for detection and quantification of DIILD.

Methods: Sprague-Dawley rats received one single dose of intratracheal bleomycin and were longitudinally imaged at day 0, 3, 7, 14, 21 and 28 post dosing, applying imaging techniques MRI and PET/CT. Bronchoalveolar lavage fluid (BALF) was analyzed for total protein and inflammatory cells. Lungs were taken for further analyses by histology, and stained for inflammation and collagen deposition.

Results: Bleomycin induced significant increase in total protein concentration and total cell count in BALF, peaking at day3 (p>0.001) and day7 (p>0.001) compared to control, respectively. The lesion measured by MRI and the FDG-PET signal in the lungs of bleomycin challenged rats was significantly increased during day3-14, peaking at day7. Two subgroups of animals were identified as low- and high responders to bleomycin challenge, by their different change in total lung volume. Both groups showed signs of inflammation initially, while at later time points the low-responder group recovered towards control, and the high-responder group showed progressive fibrosis with significant increase of lesion volume (p<0.001), compared to control.

Conclusion: Bleomycin-induced lung injury with MRI and PET readout in rats, is an adequate and translational animal model for DIILD studies. The scenario comprised different disease responses, with different fractions of inflammation and fibrosis. Thereby, this study improved the understanding biological- and imaging biomarkers in DIILD.

IBS OF OEDEMA AND FIBROSIS IN RAT DIILD
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Hyperpolarised 129-xenon diffusion-weighted MRI

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Hyperpolarised 129-xenon diffusion-weighted MRI in interstitial lung disease (Conference Abstract)

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Conference Abstract: Hyperpolarised 129Xe diffusion-weighted MRI in ILD

Hyperpolarised 129-xenon diffusion-weighted MRI in interstitial lung disease (Conference Abstract)

James Eaden, Ho-Fung Chan, Paul Hughes, Nicholas Weatherly, Matthew Austin, Laurie Smith, Jim Lithgow, Andrew Swift, Stephen Renshaw, Maya Buch, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Geoff Parker, Stephen Bianchi, Jim Wild


European Respiratory Journal 2019 54: PA3157. doi: 10.1183/13993003.congress-2019.PA3157.

Abstract

Introduction: Apparent diffusion coefficient (ADC) is a measure of gas diffusion in the airspaces, where restrictions by tissue boundaries provide information about lung microstructure down to the alveolar level. Diffusion-weighted (DW) MRI of the lung with hyperpolarised helium in idiopathic pulmonary fibrosis (IPF) has shown that ADC correlates with DLCO, KCO and CT fibrosis score (Chan, H-F. et al. Radiology 2019; doi:10.1148/radiol.2019181714) but to date no data are available on the utility of 129-xenon (129Xe) diffusion in interstitial lung disease (ILD). Aim: To evaluate the ability of 129Xe DW-MRI to distinguish between ILD subtypes.

Methods: A prospective, multicentre study of patients with ILD including drug induced ILD (DI-ILD), hypersensitivity pneumonitis (HP), IPF and connective tissue disease ILD (CTD-ILD). Hyperpolarised 129Xe DW-MRI was performed on a 1.5 T scanner and mean ADC was calculated. Results: To date, 33 patients (6 DI-ILD, 7 HP, 15 IPF, 5 CTD-ILD) have undergone baseline 129Xe DW-MRI. There was a significant difference in mean ADC between the ILD subtypes (p=0.011), with the significant difference occuring between the HP (median: 0.038cm2/s) and IPF (median: 0.048cm2/s) groups (p<0.01). Median FVC% predicted in the HP and IPF groups was 75.6% and 84.7% respectively. There was a correlation between mean ADC and DLCO (r=-0.39; p=0.03) as well as KCO (r=-0.58; p<0.01) but not FVC (r=0.24; p=0.19).

Conclusions: We demonstrate a correlation between mean 129Xe ADC and DLCO but not FVC. Our findings suggest significant differences in mean ADC between IPF and HP. Therefore, 129Xe DW-MRI could potentially have a role in differentiating changes in the airway microstructure in ILD subtypes.

CONFERENCE ABSTRACT: HYPERPOLARISED 129XE DIFFUSION-WEIGHTED MRI IN ILD
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Longitudinal change in hyperpolarised 129-xenon MR spectroscopy

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Longitudinal change in hyperpolarised 129-xenon MR spectroscopy in interstitial lung disease (Conference Abstract)

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Conference Abstract: Longitudinal change in hyperpolarised 129Xe MRS in ILD

Longitudinal change in hyperpolarised 129-xenon MR spectroscopy in interstitial lung disease (Conference Abstract)

James Eaden, Paul Hughes, Guilhem Collier, Graham Norquay, Nicholas Weatherly, Matthew Austin, Laurie Smith, Jim Lithgow, Andrew Swift, Stephen Renshaw, Maya Buch, Colm Leonard, Sarah Skeoch, Nazia Chaudhuri, Geoff Parker, Stephen Bianchi, Jim Wild


European Respiratory Journal 2019 54: PA3158 doi: 10.1183/13993003.congress-2019.PA3158 .

Abstract

Introduction: Hyperpolarised 129-xenon (129Xe) MR spectroscopy (MRS) can be used as a quantitative marker of gas exchange in interstitial lung disease (ILD). The ratio of the uptake of 129Xe in the red blood cells to the tissue/plasma (RBC:TP) has been shown to be reduced by 70% in idiopathic pulmonary fibrosis (IPF) patients when compared with healthy volunteers (Kaushik, S.S. et al. J Appl Physiol 2014; 117:577-585). In IPF, a significant decline in 129Xe RBC:TP over 12 months has been demonstrated but no significant change in DLCO or KCO (Weatherley, N.D. et al. Thorax 2018 [Epub ahead of print]).

Aim: To compare longitudinal changes in 129Xe RBC:TP with changes in FVC and DLCO between ILD subtypes.

Methods: A prospective, multicentre study of ILD patients including drug induced ILD (DI-ILD), hypersensitivity pneumonitis (HP), IPF and connective tissue disease ILD (CTD-ILD). Hyperpolarised 129Xe MRS was performed on a 1.5 T scanner.

Results: To date, 18 patients (5 DI-ILD, 5 HP, 6 IPF, 2 CTD-ILD) have undergone 129Xe MRS on two separate visits (6 weeks apart for DI-ILD/HP and 6 months apart for IPF/CTD-ILD). There was a significant difference in longitudinal change in RBC:TP between the HP and IPF groups (p=0.022). Median change in RBC:TP in the HP and IPF groups was 0.022 and -0.023 respectively. There was no significant difference in longitudinal change in FVC% predicted (p=0.79) or DLCO% predicted (p=0.39) between the ILD subtypes.

Conclusions: Our findings demonstrate that 129Xe RBC:TP has sensitivity to longitudinal change with significant differences between IPF and HP patients, whilst FVC and DLCO showed no change, suggesting that RBC:TP is more sensitive to change than PFTs in ILD.

CONFERENCE ABSTRACT: LONGITUDINAL CHANGE IN HYPERPOLARISED 129XE MRS IN ILD
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Quantitative CT and hyperpolarised 129-xenon

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Quantitative CT and hyperpolarised 129-xenon diffusion-weighted MRI in interstitial lung disease (Conference Abstract)

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Conference Abstract: Quantitative CT and hyperpolarised 129Xe dwMRI in ILD

Quantitative CT and hyperpolarised 129-xenon diffusion-weighted MRI in interstitial lung disease (Conference Abstract)

James A. Eaden, Ho-Fung Chan, Paul JC. Hughes, Nicholas D. Weatherly, Matthew Austin, Laurie J. Smith, Jim Lithgow, Smitha Rajaram, Andrew J. Swift, Stephen A. Renshaw, Ronald A. Karwoski, Brian J. Bartholmai, Colm T. Leonard, Sarah Skeoch, Nazia Chaudhuri, Geoff JM. Parker, Stephen M. Bianchi, and Jim M. Wild.


Thorax 2019;74:A79. doi: 10.1136/thorax-2019-BTSabstracts2019.131.

Abstract

Introduction: Apparent diffusion coefficient (ADC) is a diffusion-weighted (DW) MRI measure of Brownian gas diffusion in the airspaces, where restrictions by tissue boundaries provide information about lung microstructure. The mean diffusive length scale (LmD), is another DW-MRI lung microstructure measurement calculated using a stretched exponential fit method. Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) quantifies various radiological parenchymal features based on histogram signature mapping techniques and is the most widely used quantitative CT image texture analysis software in interstitial lung disease (ILD).

Aim: To evaluate the ability of hyperpolarised 129-xenon (129Xe) DW-MRI and high resolution CT (HRCT) to distinguish between ILD subtypes.

Methods: A prospective, multicentre study of patients with ILD including drug induced ILD (DI-ILD), hypersensitivity pneumonitis (HP), idiopathic pulmonary fibrosis (IPF) and connective tissue disease ILD (CTD-ILD). Hyperpolarised 129Xe DW-MRI was performed on a 1.5 T scanner. The HRCT scan was performed within a year prior to the MRI scan. Quantitative CT analysis was performed using CALIPER. Semi-quantitative visual CT analysis was performed by two consultant chest radiologists using a scoring system (table 1).

Results: To date, 32 patients (7 DI-ILD, 6 HP, 14 IPF, 5 CTD-ILD) have undergone baseline 129Xe DW-MRI and CT analysis. There was a significant difference in LmD between the HP and IPF groups (p=0.048) but this was not observed with ADC (p=0.16). Quantitative CT analysis demonstrated a significant difference between the ILD subtypes in both ground glass (GG) percent (p=0.007) and honeycombing percent (p=0.023), with the significant difference in GG% occurring between the HP and IPF groups (p=0.004). There was no significant difference between the ILD subtypes in reticulation percent (p=0.15). Semi-quantitative visual CT analysis showed a significant difference between the ILD subtypes in GG score (p=0.008), with the significant difference occurring between the HP and IPF groups (p=0.007). There was no significant difference between the ILD subtypes in the reticulation score (p=0.071) or the honeycombing score (p=0.16).

Conclusions: Our findings suggest significant differences in LmD, GG score and CALIPER GG% between IPF and HP. 129Xe DW-MRI and quantitative CT could potentially have a role in differentiating between these ILD subtypes. .

CONFERENCE ABSTRACT: QUANTITATIVE CT AND HYPERPOLARISED 129XE DWMRI IN ILD
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Oxygen-Enhanced MRI in Cystic Fibrosis

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Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

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Conference Abstract: OE-MRI in Cystic Fibrosis

Oxygen-Enhanced MRI in Cystic Fibrosis (Conference Abstract)

Marta Tibiletti, Josephine H Naish, Katharina Martini, Thomas Frauenfelder, Geoff JM Parker


British Chapter of ISMRM Meeting 2019

Abstract

Introduction:

Oxygen Enhanced MRI (OE-MRI) exploits the paramagnetic properties of molecular oxygen to modify local T1 values to explore local lung function. During a dynamic OE-MRI experiment, the subject breaths varying concentrations of O2. Various parameters can be extracted, such as the ventilated volume fraction (VVF), defined as is the fraction of lung tissue showing O2 enhancement, and the oxygen wash-in time (Tup) [1]. In this work, we calculated τup, VVF, VVF-masked Tup and compared them with pulmonary function tests in a population of healthy volunteers (HV) and cystic fibrosis (CF) subjects.

Methods:

Analysis was applied retrospectively to OE-MRI data acquired from a previously published study [1]. 20 patients with CF (20 - 40 years, 13 male) and 4 HV (27-37 y, 2 male) underwent dynamic OE-MRI on a 1.5 T Philips Achieva MRI scanner. A free-breathing protocol based on an inversion-prepared centric ordered single shot 3D-turbo field echo sequence was used. The dynamic acquisition lasted 15 min (90 volumes), during which gas was delivered at 15 l/min via a disposable non-rebreathing mask and switched at minute 2 from medical air to 100% O2, and back to air at minute 10. All images were registered to correct for breathing motion using a non-linear registration algorithm [4]. Maps of Tup were derived from the signal intensity curves for each pixel by fitting to a mono-exponential recovery function. VVF was considered positive where the Akaike information criterion favours an exponential fit over a constant function. VVF fraction, median Tu and median Tup calculated only within VVF positive pixels (masked Tup) were extracted and compared to the results from conventional spirometry (FEV1, FVC and FEV1/FVC corrected for age, height and gender). Relationships between variables were evaluated with Pearson correlation with p < 0.05 considered to indicate the presence of a statistically significant correlations.

Results:

The table present the R2 and p-values of correlation between calculated parameters and corrected spirometry results.

                         FVC pred [%]     FEV1 pred [%]   FEV1/FVC pred [%]

VVF                   0.54 (p<0.001)   0.70 (p<0.001)    0.24 (p=0.02)

Tup [s]                0.00 (p=0.89)     0.01 (p=0.59)      0.12 (p=0.12)

Masked Tup [s]  0.03 (p=0.38)     0.11 (p=0.11)       0.27 (p=0.01)

Discussion:

VVF highly correlates with measurements of lung function derived from spirometry, particularly with FEV1. Oxygen wash-in time correlated significantly with FEV1/FVC pred [%] only when non-enhancing voxels are excluded.

Conclusion:

Parameters calculated from dynamic OE-MRI are highly correlated with measurement of lung function derived from spirometry.

Reference: [1] Martini K, et al. European Radiology:1-11 (2018)

CONFERENCE ABSTRACT: OE-MRI IN CYSTIC FIBROSIS
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Ga-NODAGA-IL2 for imaging activated T-cells

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[Ga-68]Ga-NODAGA-IL2 for imaging activated T-cells. (Conference Abstract)

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Conference Abstract: 68Ga-NODAGA-IL2 for T-cell imaging

[Ga-68]Ga-NODAGA-IL2 for imaging activated T-cells. (Conference Abstract)

Antunes, I., van der Veen, E. L., Suurs, F. V., Dierckx, R. A. J. O., Lub-de Hooge, M. N., de Vries, E. G. E. & de Vries, E. F. J.


Oct-2019, In : European Journal of Nuclear Medicine and Molecular Imaging. 46, SUPPL 1, p. S702 1 p.

32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM) - Barcelona, Spain Duration: 12-Oct-2019 - 16-Oct-2019

CONFERENCE ABSTRACT: 68GA-NODAGA-IL2 FOR T-CELL IMAGING
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Tracers for non-invasive radionuclide imaging of immune

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Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

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PET tracers for immune checkpoint imaging

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Peter Wierstra, Gerwin Sandker, Erik Aarntzen, Martin Gotthardt, Gosse Adema, Johan Bussink, René Raavé & Sandra Heskamp.


EJNMMI Radiopharmacy and Chemistry volume 4,29 (2019). doi: 10.1186/s41181-019-0078-z.

Abstract

Immunotherapy with checkpoint inhibitors demonstrates impressive improvements in the treatment of several types of cancer. Unfortunately, not all patients respond to therapy while severe immune-related adverse effects are prevalent. Currently, patient stratification is based on immunotherapy marker expression through immunohistochemical analysis on biopsied material. However, expression can be heterogeneous within and between tumor lesions, amplifying the sampling limitations of biopsies. Analysis of immunotherapy target expression by non-invasive quantitative molecular imaging with PET or SPECT may overcome this issue. In this review, an overview of tracers that have been developed for preclinical and clinical imaging of key immunotherapy targets, such as programmed cell death-1, programmed cell death ligand-1, IDO1 and cytotoxic T lymphocyte-associated antigen-4 is presented. We discuss important aspects to consider when developing such tracers and outline the future perspectives of molecular imaging of immunotherapy markers..

PET TRACERS FOR IMMUNE CHECKPOINT IMAGING
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Physiologically-based pharmacokinetic modelling of transporter

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Physiologically-based pharmacokinetic modelling of transporter-mediated hepatic disposition using the imaging biomarker gadoxetate (Conference Abstract)

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Conference Abstract: PBPK modelling of transporter-mediated hepatic disposition

Physiologically-based pharmacokinetic modelling of transporter-mediated hepatic disposition using the imaging biomarker gadoxetate (Conference Abstract)

Daniel Scotcher, Sirisha Tadimalla, Adam Darwich, Sabina Ziemian, Kayode Ogungbenro, Gunnar Schütz, Steven Sourbron, Aleksandra Galetin


ISSX conference 2019.

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides a framework for in vitro-in vivo extrapolation (IVIVE) of drug disposition. However, prediction of transporter-mediated processes and tissue permeation remains challenging due to the lack of available in vivo tissue data for validation. Gadoxetate is a magnetic resonance imaging (MRI) contrast agent used clinically for hepatic lesion characterisation. As a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2), gadoxetate is being explored as a novel imaging biomarker for hepatic transporter function in context of evaluation of drug-drug interactions and drug induced liver injury [1]. The current study aimed to characterise uptake kinetics of gadoxetate in plated rat hepatocytes and develop a PBPK model to predict gadoxetate in vivo plasma and liver exposure. In vitro uptake was measured by incubating rat hepatocytes with 0.01 – 10mM gadoxetate for 0.5 – 150 min. Relevant in vitro transporter kinetic parameters were derived using a mechanistic cell model [2]. Subsequently, a novel PBPK model was developed for gadoxetate in rat, where liver uptake and cellular binding were informed by IVIVE. Gadoxetate in vivo blood, spleen and liver data obtained in the presence (n=9) and absence (n=27) of a single 10 mg/kg intravenous dose of rifampicin [3] were used for PBPK model validation/refinement. In vitro gadoxetate uptake affinity constant (Km) obtained in rat hepatocytes was 0.106 mM (n=4 rats), with saturable active transport accounting for 94% of gadoxetate cellular uptake; bidirectional transport, not saturable under current experimental conditions, was minor. The fraction unbound in hepatocytes was estimated to be 0.65. The total (Kp,u) and unbound (Kp,uu) hepatocyte:media partition coefficients were 26.0 and 16.9, respectively. The PBPK model successfully predicted gadoxetate concentrations in systemic blood and spleen and corresponding 2-fold increase in gadoxetate systemic exposure in the presence of rifampicin. In contrast, liver concentrations were under-predicted. Refinement of the PBPK model using the dynamic contrast agent enhanced (DCE)-MRI data enabled recovery of the liver profile, assuming complete and partial inhibition of hepatic uptake and biliary efflux by rifampicin, respectively. The current study demonstrates utility of imaging data in validating and refining PBPK models for prediction of transporter-mediated disposition; considerations of interpretation of quantitative DCE-MRI data to inform PBPK models are discussed.

CONFERENCE ABSTRACT: PBPK MODELLING OF TRANSPORTER-MEDIATED HEPATIC DISPOSITION
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Synthesis and Evaluation of Zirconium-89 Labelled

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Synthesis and Evaluation of Zirconium-89 Labelled and Long-Lived GLP-1 Receptor Agonists for PET Imaging

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89Zr labeled long lived GLP-1 receptor agonist

Synthesis and Evaluation of Zirconium-89 Labelled and Long-Lived GLP-1 Receptor Agonists for PET Imaging

Christian Borch Jacobsen, René Raavé, Marie Østergaard Pedersen, Pierre Adumeau, Mathieu Moreau, Ibai Valverde, Inga Bjørnsdottir, Jesper Bøggild Kristensen, Mette Finderup Grove, Kirsten Raun, James McGuire, Victor Goncalves, Sandra Heskamp, Franck Denat, Magnus Gustafsson


Nuclear Medicine and Biology 2019 Dec 4. doi: 10.1016/j.nucmedbio.2019.11.006.

Abstract

Introduction

Lately, zirconium-89 has shown great promise as a radionuclide for PET applications of long circulating biomolecules. Here, the design and synthesis of protracted and long-lived GLP-1 receptor agonists conjugated to desferrioxamine and labelled with zirconium-89 is presented with the purpose of studying their in vivo distribution by PET imaging. The labelled conjugates were evaluated and compared to a non-labelled GLP-1 receptor agonist in both in vitro and in vivo assays to certify that the modification did not significantly alter the peptides' structure or function. Finally, the zirconium-89 labelled peptides were employed in PET imaging, providing visual verification of their in vivo biodistribution.

Methods

The evaluation of the radiolabelled peptides and comparison to their non-labelled parent peptide was performed by in vitro assays measuring binding and agonistic potency to the GLP-1 receptor, physicochemical studies aiming at elucidating change in peptide structure upon bioconjugation and labelling as well as an in vivo food in-take study illustrating the compounds' pharmacodynamic properties. The biodistribution of the labelled GLP-1 analogues was determined by ex vivo biodistribution and in vivo PET imaging.

Results

The results indicate that it is surprisingly feasible to design and synthesize a protracted, zirconium-89 labelled GLP-1 receptor agonist without losing in vitro potency or affinity as compared to a non-labelled parent peptide. Physicochemical properties as well as pharmacodynamic properties are also maintained. The biodistribution in rats show high accumulation of radiolabelled peptide in well-perfused organs such as the liver, kidney, heart and lungs. The PET imaging study confirmed the findings from the biodistribution study with a significant high uptake in kidneys and presence of activity in liver, heart and larger blood vessels.

Conclusions and advances in knowledge

This initial study indicates the potential to monitor the in vivo distribution of long-circulating incretin hormones using zirconium-89 based PET.

89ZR LABELED LONG LIVED GLP-1 RECEPTOR AGONIST
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