| Title: |
Structure-based optimization and binding assays for discovery of tau PET radiotracers: synthesis and in vivo evaluation of [11C]Z-3272. |
| Authors: |
d'Orchymont, Faustine; Tong, Junchao; Kaplan, Anat Levit; Shoichet, Brian; Mathis, Chester A.; Stehouwer, Jeffrey S.; Vasdev, Neil |
| Source: |
Canadian Journal of Chemistry; 2026, Vol. 104 Issue 4, p349-355, 7p |
| Subject Terms: |
Radioactive tracers; Radiopharmaceuticals; Drug design; In vivo studies; Tauopathies; Positron emission tomography; Binding site assay |
| Abstract: |
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 [3H]Z-3272 provided Kd (nmol/L) values (n = 3) of AD = 1.2 ± 0.1, PSP = 2.7 ± 0.9, and CBD = 1.7 ± 0.1. [11C]Z-3272 was synthesized by 11C-methylation, by reaction of [11C]CH3I with 1-(5-(7-hydroxynaphthalen-2-yl)pyridin-2-yl)piperidine-4-carboxylic acid with NaHCO3 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. [11C]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 [11C]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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |