| Title: |
Structure-based optimization and binding assays for discovery of tau PET radiotracers: synthesis and in vivo evaluation of [ 11 C]Z-3272 |
| Authors: |
d'Orchymont, Faustine; Tong, Junchao; Kaplan, Anat Levit; Shoichet, Brian; Mathis, Chester A.; Stehouwer, Jeffrey S.; Vasdev, Neil |
| Contributors: |
Canada Foundation for Innovation; Azrieli Foundation; Canada Research Chairs; Ontario Research Foundation; Swiss National Foundation; Michael J. Fox Foundation for Parkinson's Research; Tau Consortium |
| Source: |
Canadian Journal of Chemistry ; volume 104, issue 4, page 349-355 ; ISSN 0008-4042 1480-3291 |
| Publisher Information: |
Canadian Science Publishing |
| Publication Year: |
2026 |
| Description: |
Human tau protein has six isoforms, differing in the number of microtubule-binding repeats. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are primarily 4-repeat (4R)-tauopathies, and Alzheimer’s disease (AD) and chronic traumatic encephalopathy are mixed 3R/4R-tau. Here, a promising lead compound for positron emission tomography (PET) imaging of non-AD tauopathies (Z5873993272; methyl-1-(5-(7-hydroxynaphthalen-2-yl)pyridin-2-yl)piperidine-4-carboxylate; Z-3272) was identified as a potential 4R-tau binding ligand through computational structure-based optimization from the 2D structure of known 4R-tau ligands, followed by iterative competition binding assays. Homologous binding assays in post-mortem AD, PSP, and CBD brain with [ 3 H]Z-3272 provided K d (nmol/L) values ( n = 3) of AD = 1.2 ± 0.1, PSP = 2.7 ± 0.9, and CBD = 1.7 ± 0.1. [ 11 C]Z-3272 was synthesized by 11 C-methylation, by reaction of [ 11 C]CH 3 I with 1-(5-(7-hydroxynaphthalen-2-yl)pyridin-2-yl)piperidine-4-carboxylic acid with NaHCO 3 in DMF at 70 °C for 3 min. The crude product was purified by semi-preparative HPLC and formulated in saline, with an overall synthesis time of 35 min from end of bombardment. [ 11 C]Z-3272 was isolated with a non-decay corrected radiochemical yield of 4 ± 1% ( n = 4), high radiochemical purity (>95%), and high molar activity (149 ± 55.5 GBq/μmol). PET imaging following bolus injection of [ 11 C]Z-3272 in rats showed high initial brain radioactivity (>2.3 standardized uptake values (SUV)) with moderate washout (∼0.7 SUV at 60 min); however, ex vivo studies revealed the rapid formation of troublesome brain penetrant radiometabolites. Medicinal chemistry optimization is underway to improve binding affinity, selectivity, and metabolic stability. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1139/cjc-2025-0058 |
| Availability: |
https://doi.org/10.1139/cjc-2025-0058; https://cdnsciencepub.com/doi/full-xml/10.1139/cjc-2025-0058; https://cdnsciencepub.com/doi/pdf/10.1139/cjc-2025-0058 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/deed.en_GB |
| Accession Number: |
edsbas.DA5C0578 |
| Database: |
BASE |