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Imaging Islets of Langerhans by Positron Emission Tomography: Quantification of Beta-Cell Mass in the Native Pancreas and the Islet Graft
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 and 2 Diabetes Mellitus are a growing health problem throughout the world. There is an increasing  need for methodologies, which are both reliable and non-invasive to measure the amount of insulin-producing tissue (Beta-cell mass, or BCM), as well as rapidly quantify changes in the BCM due to the onset of disease, beta-cell replacement therapy, or other treatments.

Positron Emission Tomography (PET) is a non-invasive, quantitative functional imaging technique which can be used to study dynamical or static processes inside the body.

In this thesis, we present a study protocol for in vivo imaging of the most common form of beta- cell replacement therapy; islet transplantation. Islets were labeled with the PET tracer, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG), and administered intra-portally, while the recipient was monitored by PET/CT. The hepatic distribution of the islets was highly heterogeneous, and around 25% (human) or 50% (porcine) of the administered islets could not be found in the liver after completed transplantation, confirming previous reports of considerable cell injury during the procedure leading to low hepatic engraftment.

Native BCM in the pancreas can potentially be quantified using a PET tracer with sufficiently high specificity, but the major obstacle is the relative low amounts of insulin producing tissue (only 1-2% of the pancreatic volume). Two tetrabenazine analogues, [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, are ligands to VMAT2, which is expressed in islet tissue. Both analogues were investigated and characterized as potential BCM imaging agents both in vitro and in vivo.  Both tracers exhibited high preferential binding to islet tissue compared to exocrine pancreatic tissue. However, the specificity was not high enough to overcome the obscuring exocrine signal in vivo (7-10% of the signal originating from specific islet tracer uptake).

This thesis demonstrates that it is possible to quantitatively assess islet transplantation by PET imaging. In vivo determination of native pancreatic BCM is, in theory, possible with both [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, but tracer analogues with higher islet specificity is needed for quantification of smaller BCM changes with physiological impact.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 635
Keywords [en]
Positron Emission Tomography, [18F]FDG, dihydrotetrabenazine, Islet transplantation, IBMIR, beta-cell mass
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-136372ISBN: 978-91-554-7978-7 (print)OAI: oai:DiVA.org:uu-136372DiVA, id: diva2:377139
Public defence
2011-02-04, Rosénsalen, Akademiska Sjukhuset, Ingång 95/96, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-01-14 Created: 2010-12-12 Last updated: 2011-03-11
List of papers
1. Positron emission tomography: A real-time tool to quantify early islet engraftment in a preclinical large animal model
Open this publication in new window or tab >>Positron emission tomography: A real-time tool to quantify early islet engraftment in a preclinical large animal model
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2007 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, no 7, p. 893-898Article in journal (Refereed) Published
Abstract [en]

Background. Clinical islet transplantation is currently being explored as a therapeutic option for persons with type I diabetes and hypoglycemic unawareness. Techniques to monitor graft survival are urgently needed to optimize the procedure. Therefore, the objective of the present study was to develop a technique for imaging survival of transplanted islets in the peritransplant and early posttransplant phase.

Methods. Isolated porcine islets were labeled in vitro with 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) and infused intraportally into anesthetized pigs (n=10). Dynamic examination was performed on a positron emission tomography/computed tomography hybrid system.

Results. More than 95% of the radioactivity was confined to the islets at the time of transplantation. The peak percentage of infused radioactivity within the liver, quantified at the end of the islet infusion, was only 54±5.1%. The distribution of the radioactivity in the liver was found to be heterogeneous. A whole-body examination showed no accumulation in the lungs or brain; extrahepatic radioactivity was, except urinary excretion, evenly distributed in the pig body.

Conclusions. Our results imply that almost 50% of the islets were damaged to the extent that the FDG contained was release within minutes after intraportal transplantation. The distribution of radioactivity without accumulation in the brain indicates that the activity is released from lysed islet cells in the form of [18F]FDG-6P rather than native [18F]FDG. The presented technique shows promise to become a powerful and quantitative tool, readily available in the clinic, to evaluate initial islet engraftment and survival.

Keywords
Imaging, Islets, PET scanning, Transplantation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-14994 (URN)10.1097/01.tp.0000284730.86567.9f (DOI)000250232600014 ()17984843 (PubMedID)
Available from: 2008-06-05 Created: 2008-06-05 Last updated: 2017-12-11Bibliographically approved
2. Visualization of early engraftment in clinical islet transplantation by positron-emission tomography
Open this publication in new window or tab >>Visualization of early engraftment in clinical islet transplantation by positron-emission tomography
2007 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 356, no 26, p. 2754-2755Article in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-103621 (URN)000247564500035 ()17596618 (PubMedID)
Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2017-12-13Bibliographically approved
3. Positron emission tomography in clinical islet transplantation
Open this publication in new window or tab >>Positron emission tomography in clinical islet transplantation
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2009 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 9, no 12, p. 2816-2824Article in journal (Refereed) Published
Abstract [en]

The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants. A fraction of the islets (23%) were labeled with 18F-fluorodeoxyglucose ([(18)F]FDG) and carefully mixed with unlabeled islets just prior to intraportal transplantation. The peak radioactivity concentration in the liver was found at 19 min after start of islet infusion and corresponded to only 75% of what was expected, indicating that islets are lost during the transplantation procedure. No accumulation of radioactivity was found in the lungs. A nonphysiological peak of C-peptide was found in plasma during and immediately after transplantation in all subjects. Distribution in the liver was heterogeneous with wide variations in location and concentration. Islets found in areas with concentrations of >400 IEQ/cc liver tissue varied between 1% and 32% of the graft in different subjects. No side effects attributed to the PET/CT procedure were found. Clinical outcome in all patients was comparable to that previously observed indicating that the [(18)F]FDG labeling procedure did not harm the islets. The technique has potential to be used to assess approaches to enhance islet survival and engraftment in clinical transplantation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-111860 (URN)10.1111/j.1600-6143.2009.02844.x (DOI)000272127600023 ()19845588 (PubMedID)
Available from: 2009-12-28 Created: 2009-12-28 Last updated: 2017-12-12Bibliographically approved
4. In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass
Open this publication in new window or tab >>In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass
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2010 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, no 3, p. 357-363Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: The positron emission tomography (PET) tracer 9-[(18)F]fluoroethyl-(+)-dihydrotetrabenazine ([(18)F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass.

METHODS: Three pigs were intravenously administered [(18)F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k(D) and B(max) were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls.

RESULTS: [(18)F]-FE-(+)-DTBZ had a k(D) of 3.5+/-1.0 nM, a B(max) of 382+/-108 fmol/mg protein and a specificity of 89+/-1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone.

CONCLUSIONS: [(18)F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [(18)F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.

Keywords
Positron emission tomography, DTBZ, Beta-cell mass, VMAT2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-136369 (URN)10.1016/j.nucmedbio.2009.12.004 (DOI)000276551800013 ()20346875 (PubMedID)
Available from: 2010-12-12 Created: 2010-12-12 Last updated: 2017-12-11Bibliographically approved
5. Decreased defluorination by using the novel beta cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET
Open this publication in new window or tab >>Decreased defluorination by using the novel beta cell imaging agent [18F]FE-DTBZ-d4 in pigs examined by PET
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Fluorine-18 DTBZ-analogues, which selectively targets the vesicular monoamine transporter 2 (VMAT2), have been extensively studied for in vivo quantification of beta cell mass by positron emission tomography (PET).  This study describes a novel deuterated radioligand [18F]FE-(+)-DTBZ-d4, aimed to increase the stability against in vivo defluorination previously observed for [18F]FE-(+)-DTBZ.

Methods: [18F]FE-(+)-DTBZ-d4 was synthesized by alkylation of desmethyl -(+)-DTBZ precursor with deuterated  [18F]fluoroethyl bromide ([18F]FCD2CD2Br). Radioligand affinity and specificity to VMAT2 was assessed by an in vitro saturation homogenate binding assay using human endocrine and exocrine pancreatic tissues. In vivo PK/PD was studied in a porcine model by PET/CT. The rate of defluorination was quantified by compartmental modeling and contrasted against defluorination of the non-deuterated analogue.

Results: [18F]FE-DTBZ-d4 was produced in good radiochemical yield (3.0-1.7 GBq) in 100 min. Radiochemical purity of the formulated product was > 98% for up to 5h. The in vitro Binding Potential (BP) for VMAT2 in islet tissue was 27.0±8.8. The BP was lower in exocrine tissue (1.7±1.0) in addition to a close to three-fold decrease in specificity. The rate of in vivo defluorination was decreased significantly (kdefluorination= 0.0016±0.0007) compared to the non-deuterated analogue (kdefluorination= 0.012±0.002), resulting in a more than six-fold increase in half-life stability.

Conclusion: [18F]FE-(+)-DTBZ-d4 has favorable pharmacokinetic (PK) properties for VMAT2 imaging, in addition to gaining significantly increased stability against defluorination. The in vitro islet BP and specificity was lower compared to a non-deuterated analogue but the islet/exocrine BP ratio was unchanged, potentially allowing for improved target tissue discrimination.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-136370 (URN)
Available from: 2010-12-12 Created: 2010-12-12 Last updated: 2018-01-12

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