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The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.

ABSTRACT: BACKGROUND:The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand. METHODS:The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments. RESULTS:The radiochemical purity of the resulting radioligand [11C]AZ12204657 was >?98%, with high molar activity (MA), 1351?±?575?GBq/?mol (n?=?18). The radiochemical purity of [3H]AZ12204657 was >?99% with MA of 2?GBq/?mol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was >?10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy. CONCLUSION:We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.

SUBMITTER: Jahan M

PROVIDER: S-EPMC6306373 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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The development of a GPR44 targeting radioligand [<sup>11</sup>C]AZ12204657 for in vivo assessment of beta cell mass.

Jahan Mahabuba M Johnström Peter P Selvaraju Ram K RK Svedberg Marie M Winzell Maria Sörhede MS Bernström Jenny J Kingston Lee L Schou Magnus M Jia Zhisheng Z Skrtic Stanko S Johansson Lars L Korsgren Olle O Farde Lars L Halldin Christer C Eriksson Olof O

EJNMMI research 20181227 1

<h4>Background</h4>The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand.<h4>Methods</h4>The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using <sup>11</sup>C- or <sup>3</sup>H-labeled methyl iodide ([<sup>11</sup>C/<sup>3</sup>H]CH<sub>3</sub>I) in one step, and t ...[more]

PMID: 30588560

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Project description: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.

Dataset Information

The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.

Publications

The development of a GPR44 targeting radioligand [<sup>11</sup>C]AZ12204657 for in vivo assessment of beta cell mass.

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