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  • br Manganese based imaging probes

    2021-09-15


    Manganese-based imaging probes
    Imaging of vesicular monoamine transporter 2 (VMAT2)
    Imaging of sulfonylurea receptor 1 (SUR1) In mammals, insulin secretion is mediated by the membrane potential of pancreatic β-cells. Increases in glucose levels lead to blocking of ATP-sensitive potassium channels (KATP channels) in the plasma membrane, which lead to membrane depolarization, increases in calcium influx, and subsequent insulin granule exocytosis. Hetero-octameric KATP channels are composed of four inward-rectifier K+ channel subunits and four sulphonylurea receptor subunits (SUR1, SUR2A, or SUR2B) [22,77,78]. By binding to SUR1 [79], sulfonylureas are used in patients with T2DM to mitigate T2DM symptoms by stimulating insulin secretion even in the absence of glucose [80]. Although SURs are also expressed by other endocrine pancreatic Methoxyresorufin [81], sulfonylureas, especially glibenclamide (glyburide) and tolbutamide, have emerged as attractive candidates for BCM imaging [[82], [83], [84], [85]]. Since the original glibenclamide molecule underwent hepatic clearance and radiolabeled glibenclamide therefore had high liver uptake, it was unsuitable for islet imaging [86]. Therefore, novel glibenclamide derivatives targeting pancreatic β-cells with optimized pharmacokinetics and biodistributions have been developed. In 2007, Schneider et al. synthesized a high affinity glibenclamide-glucose conjugate by adding new moieties to the glibenclamide structure, and found that this new conjugate had enhanced hydrophilicity (a 12-fold increase) and preserved its high binding affinity to SUR1 in vitro. Furthermore, in vivo studies verified that this compound was cleared much faster from circulation, mainly because of its lower plasma protein binding [87]. Therefore, this glucose conjugate could serve as a potential lead compound for designing other glibenclamide derivatives and for β-cell imaging by targeting SURs. Repaglinide, an oral medication for T2DM, induces insulin secretion by closing ATP-dependent potassium channels and by opening the calcium channels in β-cell membranes [88]. Repaglinide has also been explored for noninvasive PET imaging of β-cells [[89], [90], [91]]. More recently, Kimura et al. synthesized several novel mitiglinide derivatives and found that one of these compounds, (+)-(S)-o-FMIT, showed the highest affinity for SUR1 and specifically accumulated in pancreatic β-cells as revealed by ex vivo autoradiography, suggesting that (+)-(S)-o-18F-FMIT could be a candidate PET tracer for in vivo molecular imaging of pancreatic β-cells [92]. However, several other radiolabeled SUR1 ligands had low, non-specific concentration in the pancreas but high uptake in adjacent organs [89,93].
    Imaging of glucagon-like peptide-1 receptor (GLP-1R)
    Molecular imaging with β-cell specific antibodies β-Cell specific antibodies, or humanized high affinity antibody fragments, may meet the requirements of β-cell specific imaging after conjugation with radioactive isotopes [[120], [121], [122]]. Radiolabeled monoclonal antibodies (mAbs) targeting pancreatic β-cells have been reported by several studies [122,123]. Therefore, by utilizing these mAbs which specifically bind to insulin-producing β-cells, development of antibody-based imaging probes has shown enormous promise and could potentially result in important tools for evaluating BCM. Transmembrane protein 27 (TMEM27) stimulates pancreatic β-cell proliferation, is predominantly expressed on the β-cell surface [124], and thus may serve as a potential marker for pancreatic BCM [125]. Using a mAb (8/9-mAb) specific to human TMEM27 (hTMEM27), Rudin and colleagues reported multimodal imaging strategies to target β-cells on human samples and in animal models. 89Zr-8/9-mAb showed high signal-to-background contrast in subcutaneous insulinoma models one day after tracer injection, and fluorescently-labeled 8/9-mAb showed β-cell specific staining on both human and mouse pancreatic sections [126]. However, the specificity of 8/9-mAb for human TMEM27 may limit its use for BCM assessment in preclinical diabetic animal models. Cross species-selective antibodies against TMEM27 are still needed to further evaluate the potential value of TMEM27 in noninvasive β-cell imaging.