| 1. |
- Schlein, Eva, et al.
(författare)
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Synthesis and evaluation of fluorine-18 labelled tetrazines as pre-targeting imaging agents for PET
- 2024
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Ingår i: EJNMMI Radiopharmacy and Chemistry. - : Springer Nature. - 2365-421X. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The brain is a challenging target for antibody-based positron emission tomography (immunoPET) imaging due to the restricted access of antibody-based ligands through the blood-brain barrier (BBB). To overcome this challenge we have previously developed bispecific antibody ligands that pass through the BBB via receptor-mediated transcytosis. These ligands, when radiolabelled, can be used for brain imaging with high affinity and specificity, but their long residence time in the blood and brain can be challenging for their use as PET radioligands. This could be solved by using a two-step approach which involves the administration of a tagged antibody that accumulates at the target site in the brain and then clears from the blood, followed by administration of a radiolabelled molecule, with fast kinetics. This radiolabelled molecule can couple to the tagged antibody and thereby make the antibody localisation visible by PET imaging. The in vivo linkage can be achieved using the inverse electron demand Diels-Alder reaction (IEDDA), with trans-cyclooctene (TCO) and tetrazine groups participating as reactants.In this study, two 18F-labelled tetrazines were synthesized and evaluated for their potential as agents for pre-targeted imaging, i.e. for their ability to rapidly enter the brain and then, if non-bound, be sufficiently cleared with low background retention. The two compounds, a methyl tetrazine [18F]MeTz and an H-tetrazine [18F]HTz were radiolabelled using a two-step procedure via [18F]F-Py-TFP synthesized on solid support followed by amidation with amine-bearing tetrazines, resulting in radiochemical yields of 24% and 22%, respectively, and a radiochemical purity of > 96%. In vivo PET imaging was performed to assess their suitability for in vivo pre-targeting. Time-activity curves from PET-scans revealed that the [18F]MeTz had the most favourable profile for an imaging agent for pre-targeting, due to its fast and homogenous brain distribution and rapid clearance from the brain.
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| 2. |
- Battisti, Umberto Maria, et al.
(författare)
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Ellagic Acid and Its Metabolites as Potent and Selective Allosteric Inhibitors of Liver Pyruvate Kinase
- 2023
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Liver pyruvate kinase (PKL) has recently emerged as a new target for non-alcoholic fatty liver disease (NAFLD), and inhibitors of this enzyme could represent a new therapeutic option. However, this breakthrough is complicated by selectivity issues since pyruvate kinase exists in four different isoforms. In this work, we report that ellagic acid (EA) and its derivatives, present in numerous fruits and vegetables, can inhibit PKL potently and selectively. Several polyphenolic analogues of EA were synthesized and tested to identify the chemical features responsible for the desired activity. Molecular modelling studies suggested that this inhibition is related to the stabilization of the PKL inactive state. This unique inhibition mechanism could potentially herald the development of new therapeutics for NAFLD.
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