title: Synthesis and labeling of a piperazine-based library of ¹¹C-labeled ligands for imaging of the vesicular acetylcholine transporter.
abstract: The cholinergic system is involved in neurodegenerative diseases, and visualization of cholinergic innervations with positron emission tomography (PET) would be a useful tool in understanding these diseases. A ligand for the vesicular acetylcholine transporter (VAChT), acknowledged as a marker for cholinergic neurons, could serve as such a PET tracer. The aim was to find a VAChT PET tracer using a library concept to create a small but diverse library of labeled compounds. From the same precursor and commercially available aryl iodides 6a-f, six potential VAChT PET tracers, [(11)C]-(±)5a-f, were (11)C-labeled by a palladium (0)-mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [(11)C]-(±)5a-f were obtained in radiochemical purities >95% with decay-corrected radiochemical yields and specific radioactivities between 4-25% and 124-597 GBq/µmol, respectively. Autoradiography studies were then conducted to assess the compounds binding selectivity for VAChT. Labeled compounds [(11)C]-(±)5d and [(11)C]-(±)5e showed specific binding but not enough to permit further preclinical studies. To conclude, a general method for a facile synthesis and labeling of a small piperazine-based library of potential PET tracers for imaging of VAChT was shown, and in upcoming work, another scaffold will be explored using this approach.
authors.affiliation: Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Box 574, SE-751 23, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Bergman
authors.forename: Sergio
authors.initials: S
authors.lastname: Estrada
authors.forename: Håkan
authors.initials: H
authors.lastname: Hall
authors.forename: Rashidur
authors.initials: R
authors.lastname: Rahman
authors.forename: Andreas
authors.initials: A
authors.lastname: Blomgren
authors.forename: Mats
authors.initials: M
authors.lastname: Larhed
authors.forename: Marie
authors.initials: M
authors.lastname: Svedberg
authors.forename: Alf
authors.initials: A
authors.lastname: Thibblin
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wångsell
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
mesh_terms: D002250:Carbon Radioisotopes / Q000737:chemistry; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography; D054852:Small Molecule Libraries / Q000138:chemical synthesis*; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis*
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D010879:Piperazines; D054852:Small Molecule Libraries; D050494:Vesicular Acetylcholine Transport Proteins
keywords: 11C-labeling; PET; carbonylation; library; vesamicol; vesicular acetylcholine transporter