Synthesis and labeling of a piperazine-based library of 11C-labeled ligands for imaging of the vesicular acetylcholine transporter

• Published in: Journal of labelled compounds & radiopharmaceuticals 2014-06, Vol.57 (8), p.525-532
• Main Authors: Bergman, Sara, Estrada, Sergio, Hall, Håkan, Rahman, Rashidur, Blomgren, Andreas, Larhed, Mats, Svedberg, Marie, Thibblin, Alf, Wångsell, Fredrik, Antoni, Gunnar
• Format: Article
• Language: English
• Subjects: 11C-labeling; Carbon Radioisotopes - chemistry; carbonylation; library; Ligands; PET; Piperazines - chemical synthesis; Positron-Emission Tomography; Small Molecule Libraries - chemical synthesis; vesamicol; Vesicular Acetylcholine Transport Proteins - analysis; vesicular acetylcholine transporter
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.3208

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, [11C]‐(±)5a–f, were 11C‐labeled by a palladium (0)‐mediated aminocarbonylation, utilizing a standard protocol. The labeled compounds [11C]‐(±)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 [11C]‐(±)5d and [11C]‐(±)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 A library of six piperazine‐based ligands for the vesicular acetylcholine transporter were synthesized and labeled from a common precursor, commercially available aryl iodides and [11C]carbon monoxide. Labeled compounds were isolated with radiochemical yields ranging from 4% to 25% and with specific radioactivities between 124 and 597 GBq/µmol. As a simple preclinical evaluation of the labeled compounds, their binding potential to VAChT was assessed by autoradiography.