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[摘要]：[C-11]N-Methyl lansoprazole ([C-11]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [C-11]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [C-11]MeI), 99% radiochemical purity, and 16095 Ci/mmol specific activity (n = 5). Log P was determined to be 2.18. A lack of brain uptake in rodent inicroPET imaging revealed [C-11]NML to be a,substrate for the rodent permeability-glycoprotein 1 (PGP) transporter, but this could be overcome by, pretreating with cyclosporin A to block the PGP. Contrastingly, [C-11]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [C-11]NML uptake in the healthy primate brain of similar to 1600 nCi/cc maximum at 3 min followed by rapid egress to 500 nCi/cc. Comparative autoradiography between wild type rats and transgenic rats expressing human tau (hTau +/+) revealed 12% higher uptake of [C-11]NML in the cortex of brains expressing human tau. Further autoradiography with tau positive brain samples from progressive supranuclear palsy (PSP) patients revealed colocalization of [C-11]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K-d and Bmax values of [C-11]NML as 700 pM and 0.214 fmol/mu g, respectively. |
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