ArticleEuropean journal of pharmacology2015
In vitro and ex vivo characterization of (-)-TZ659 as a ligand for imaging the vesicular acetylcholine transporter.
Article in European journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 7 citations in OpenAlex.
- The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review.Molecules (Basel, Switzerland) · 2024Review
- In vitro characterization of [European journal of pharmacology · 2021Article
- Radiosynthesis and evaluation of a fluorine-18 labeled radioligand targeting vesicular acetylcholine transporter.Bioorganic & medicinal chemistry letters · 2018Article
- Exploration of Sulfur-Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain.ChemMedChem · 2018Article
- Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate.Organic & biomolecular chemistry · 2017Article
- Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates.Nuclear medicine and biology · 2016Article
- Synthesis and biological characterization of a promising F-18 PET tracer for vesicular acetylcholine transporter.Bioorganic & medicinal chemistry · 2015Article
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8 authors at 2 institutions in 1 country.
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Abstract
The loss of cholinergic neurons and synapses relates to the severity of dementia in several neurodegenerative pathologies; and the vesicular acetylcholine transporter (VAChT) provides a reliable biomarker of cholinergic function. We recently characterized and (11)C-labeled a new VAChT inhibitor, (-)-TZ659. Here we report the in vitro and ex vivo characterization of (-)-TZ659. A stably transfected PC12(A123.7) cell line which expresses human VAChT (hVAChT) was used for the in vitro binding characterization of (-)-[(3)H]TZ659. A saturated binding curve was obtained with Kd=1.97±0.30nM and Bmax=3240±145.9fmol/mg protein. In comparison, a PC12(A123.7) cell line that expresses mutant hVAChT showed decreased binding affinity (Kd=15.94±0.28nM). Competitive binding assays using a panel of other CNS ligands showed no inhibition of (-)-[(3)H]TZ659 binding. On the other hand, binding inhibitions were observed only using VAChT inhibitors (Ki=0.20-31.35nM). An in vitro assay using rat brain homogenates showed that (-)-[(3)H]TZ659 had higher binding in striatum than in cerebellum, with a target: non-target ratio>3.46. Even higher ex vivo striatum-to-cerebellum ratios (9.56±1.11) were observed using filtered homogenates of brain tissue after rats were injected intravenously with (-)-[(11)C]TZ659. Ex vivo autoradiography of (-)-[(11)C]TZ659 confirmed high striatal uptake, with a consistently high striatum-to-cerebellum ratio (2.99±0.44). In conclusion, (-)-TZ659 demonstrated high potency and good specificity for VAChT in vitro and in vivo. These data suggest that (-)-[(11)C]TZ659 may be a promising PET tracer to image VAChT in the brain.
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