Evaluation of [11C]N-Methyl Lansoprazole as a Radiopharmaceutical for PET Imaging of Tau Neurofibrillary Tangles

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• 作者：Xia Shao ; Garrett M. Carpenter ; Timothy J. Desmond ; Phillip Sherman ; Carole A. Quesada ; Maria Fawaz ; Allen F. Brooks ; Michael R. Kilbourn ; Roger L. Albin ; Kirk A. Frey ; Peter J. H. Scott
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：3
• 期：11
• 页码：936-941
• 全文大小：335K
• 年卷期：v.3,no.11(November 8, 2012)
• ISSN：1948-5875

文摘

[¹¹C]N-Methyl lansoprazole ([¹¹C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [¹¹C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY, based upon [¹¹C]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 microPET imaging revealed [¹¹C]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, [¹¹C]NML was not found to be a substrate for the primate PGP, and microPET imaging in rhesus revealed [¹¹C]NML uptake in the healthy primate brain of 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 [¹¹C]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 [¹¹C]NML with tau NFTs identified using modified Bielschowsky staining. Finally, saturation binding experiments with heparin-induced tau confirmed K_d and Bmax values of [¹¹C]NML as 700 pM and 0.214 fmol/渭g, respectively.

Keywords:

Alzheimer's disease; tauopathies; neuroimaging; positron emission tomography imaging; carbon-11