Theranostics 2020; 10(1):398-410. doi:10.7150/thno.33410

Research Paper

PET/MRI enables simultaneous in vivo quantification of β-cell mass and function

Filippo C. Michelotti1, Gregory Bowden1, Astrid Küppers2, Lieke Joosten3, Jonas Maczewsky4, Volker Nischwitz2, Gisela Drews4, Andreas Maurer1,5, Martin Gotthardt3, Andreas M. Schmid1,*, Bernd J. Pichler1,5,*✉

1. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
2. Forschungszentrum Jülich GmbH, Central Institute of Engineering, Electronics and Analytics, Jülich, Germany,
3. Radboud University Medical Center, Department of Radiology and Nuclear Medicine, Nijmegen, The Netherlands
4. Experimental Diabetology, Phamacology, Pharmaceutical Institute, Eberhard Karls University Tübingen, Tübingen, Germany
5. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Germany
*Authors contributed equally

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Citation:
Michelotti FC, Bowden G, Küppers A, Joosten L, Maczewsky J, Nischwitz V, Drews G, Maurer A, Gotthardt M, Schmid AM, Pichler BJ. PET/MRI enables simultaneous in vivo quantification of β-cell mass and function. Theranostics 2020; 10(1):398-410. doi:10.7150/thno.33410. Available from http://www.thno.org/v10p0398.htm

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Abstract

Non-invasive imaging of β-cells represents a desirable preclinical and clinical tool to monitor the change of β-cell mass and the loss of function during pre-diabetic stages. Although it is widely accepted that manganese (Mn) ions are actively gated by voltage-dependent calcium channels (VDCC) in response to glucose metabolism, little is known on its specificity in vivo for quantification of islet β-cell function using Mn and magnetic resonance imaging (MRI). On the other hand, glucagon-like-peptide-1 receptor (GLP-1R) represents a validated target for the estimation of β-cell mass using radiolabeled exendin-4 (Ex4) and positron emission tomography (PET). However, a multiparametric imaging workflow revealing β-cell mass and function quantitatively is still missing.

Methods: We developed a simultaneous PET/MRI protocol to comprehensively quantify in vivo changes in β-cell mass and function by targeting, respectively, GLP-1R and VDCC coupled with insulin secretion. Differences in the spatial distribution of Mn and radiolabeled Ex4 were monitored overtime in native and transgenic pancreata, characterized by spontaneous pancreatic neuroendocrine tumor development. Follow-up with mass spectrometry imaging (MSI) and autoradiography allowed the ex vivo validation of the specificity of Mn and PET tracer uptake and the detection of endogenous biometals, such as calcium and zinc, throughout the endocrine and exocrine pancreas.

Results: Our in vivo data based on a volumetric PET/MRI readout for native pancreata and insulinomas connects uptake of Mn measured at early imaging time points to high non-specific binding by the exocrine tissue, while specific retention was only found 24 h post injection. These results are supported by cross-validation of the spatial distribution of exogenous 55Mn and endogenous 44Ca and 64Zn as well with the specific internalization of the radiolabeled peptide targeting GLP-1R.

Conclusion: Simultaneous PET/MR imaging of the pancreas enabled the comprehensive in vivo quantification of β-cell function and mass using Mn and radiolabeled Ex4. Most important, our data revealed that only late time-point measurements reflect the Mn uptake in the islet β-cells, while early time points detect non-specific accumulation of Mn in the exocrine pancreas.

Keywords: PET, MRI, PET/MRI, β-cell function, β-cell mass, VDCC, GLP-1R.