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- Fredriksson, A., et al.
(författare)
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Labeling of human C-peptide by conjugation with N-succinimidyl-4- F-18 fluorobenzoate
- 2001
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Ingår i: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 44:7, s. 509-519
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Tidskriftsartikel (refereegranskat)abstract
- We have labeled proinsulin connecting peptide (C-peptide) with fluorine-18 (t(1/2) = 109.7min) in order to perform in vivo biodistribution and pharmacokinetic studies with position emission tomography (PET). This study reports the optimization of the conjugation labeling in the N-terminal with N-succinimidyl-4-[F-18]fluorobenzoate ([F-18]SFB). In preparative runs N-4-[F-18]fluorobenzoyl-C-peptide ([F-18]FB-C-peptide) was produced in 8-12% decay-corrected yields, counted from resolubilized [F-18]F-, in less than 5h. The specific radioactivity of [F-18]FB-C-peptide, determined using ELISA for one of the preparations, was around 70 GBq/mu mol at end of synthesis.
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- Eriksson, Olof, et al.
(författare)
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In Vivo Visualization of beta-Cells by Targeting of GPR44
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:2, s. 182-192
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Tidskriftsartikel (refereegranskat)abstract
- GPR44 expression has recently been described as highly beta-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C-11]AZ12204657, was evaluated for visualization of beta-cells in pigs and non-human primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess beta-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [C-11]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [C-11]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [C-11]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [C-11]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic beta-cells by targeting the protein GPR44.
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- Hellstrom-Lindahl, E., et al.
(författare)
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Toward molecular imaging of the free fatty acid receptor 1
- 2017
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 54:7, s. 663-668
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Tidskriftsartikel (refereegranskat)abstract
- Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H-3]AZ1, [H-3]AZ2 and [H-3]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. [H-3]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H-3]AZ2 and [H-3]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.
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- Jahan, M., et al.
(författare)
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Synthesis and biological evaluation of [C-11]AZ12504948; a novel tracer for imaging of glucokinase in pancreas and liver
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 42:4, s. 387-394
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Glucokinase (GK) is potentially a target for imaging of islets of Langerhans. Here we report the radiosynthesis and preclinical evaluation of the GK activator, [C-11]AZ12504948, for in vivo imaging of GK. Methods: [C-11]AZ12504948 was synthesized by O-methylation of the precursor, AZ125555620, using carbon-11 methyl iodide ([C-11]CH3I).Preclinical evaluation was performed by autoradiography (ARC) of human tissues and PET/CT studies in pig and non-human primate. Result: [C-11]AZ12504948 was produced in reproducible good radiochemical yield in 28-30 min. Radiochemical purity of the formulated product was >98% for up to 2 h with specific radioactivities 855 +/- 209 GBq/mu mol (n = 8). The preclinical evaluation showed some specificity for GK in liver, but not in pancreas. Conclusion:[C-11]AZ12504948 images GK in liver, but the low specificity impedes the visualization of GK in pancreas. Improved target specificity is required for further progress using PET probes based on this class of GK activators.
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