Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography
The fibrillary aggregation of α-synuclein is a hallmark of Parkinson’s disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinicall...
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2025-07-01
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| author | Haiyang Zhao Tianyu Huang Dhruva D. Dhavale Jennifer Y. O’Shea Zsofia Lengyel-Zhand Dinahlee Saturnino Guarino Jiwei Gu Xuyi Yue Ying-Hwey Nai Hao Jiang Marshall G. Lougee Vinayak V. Pagar Hee Jong Kim Benjamin A. Garcia E. James Petersson Chester A. Mathis Paul T. Kotzbauer Joel S. Perlmutter Robert H. Mach Zhude Tu |
| author_facet | Haiyang Zhao Tianyu Huang Dhruva D. Dhavale Jennifer Y. O’Shea Zsofia Lengyel-Zhand Dinahlee Saturnino Guarino Jiwei Gu Xuyi Yue Ying-Hwey Nai Hao Jiang Marshall G. Lougee Vinayak V. Pagar Hee Jong Kim Benjamin A. Garcia E. James Petersson Chester A. Mathis Paul T. Kotzbauer Joel S. Perlmutter Robert H. Mach Zhude Tu |
| author_sort | Haiyang Zhao |
| collection | DOAJ |
| description | The fibrillary aggregation of α-synuclein is a hallmark of Parkinson’s disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new <i>N</i>-(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their α-synuclein binding affinity is reported here. Compounds <b>7f</b>, <b>7j</b>, and <b>8i</b> exhibited high affinity for α-synuclein and were selected for <sup>11</sup>C, <sup>18</sup>F, <sup>125</sup>I, or <sup>3</sup>H radiolabeling. A photoaffinity variant, <b>TZ-CLX</b>, structurally related to <b>7j</b> and <b>8i</b>, demonstrated preferential binding to the C-terminal region of α-synuclein fibrils. PET brain imaging studies using [<sup>11</sup>C]<b>7f</b>, [<sup>18</sup>F]<b>7j</b>, and [<sup>11</sup>C]<b>8i</b> in non-human primates indicated that these three α-synuclein PET tracers penetrated the blood–brain barrier. Both [<sup>11</sup>C]<b>7f</b> and [<sup>18</sup>F]<b>7j</b> showed more favorable brain washout pharmacokinetics than [<sup>11</sup>C]<b>8i</b>. In vitro binding assays showed that [<sup>125</sup>I]<b>8i</b> is a very potent α-synuclein radioligand, with K<sub>d</sub> values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the <i>N</i>-(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting α-synuclein aggregates in vivo. |
| format | Article |
| id | doaj-art-e66bddb3c171467f81bb39c33b8d0dd4 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-e66bddb3c171467f81bb39c33b8d0dd42025-08-20T03:58:31ZengMDPI AGCells2073-44092025-07-011414110810.3390/cells14141108Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission TomographyHaiyang Zhao0Tianyu Huang1Dhruva D. Dhavale2Jennifer Y. O’Shea3Zsofia Lengyel-Zhand4Dinahlee Saturnino Guarino5Jiwei Gu6Xuyi Yue7Ying-Hwey Nai8Hao Jiang9Marshall G. Lougee10Vinayak V. Pagar11Hee Jong Kim12Benjamin A. Garcia13E. James Petersson14Chester A. Mathis15Paul T. Kotzbauer16Joel S. Perlmutter17Robert H. Mach18Zhude Tu19Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Radiology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Neurology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Neurology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Radiology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Radiology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Radiology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Radiology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Neurology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Neurology, Washington University School of Medicine, St Louis, MO 63110, USADepartment of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Radiology, Washington University School of Medicine, St Louis, MO 63110, USAThe fibrillary aggregation of α-synuclein is a hallmark of Parkinson’s disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new <i>N</i>-(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their α-synuclein binding affinity is reported here. Compounds <b>7f</b>, <b>7j</b>, and <b>8i</b> exhibited high affinity for α-synuclein and were selected for <sup>11</sup>C, <sup>18</sup>F, <sup>125</sup>I, or <sup>3</sup>H radiolabeling. A photoaffinity variant, <b>TZ-CLX</b>, structurally related to <b>7j</b> and <b>8i</b>, demonstrated preferential binding to the C-terminal region of α-synuclein fibrils. PET brain imaging studies using [<sup>11</sup>C]<b>7f</b>, [<sup>18</sup>F]<b>7j</b>, and [<sup>11</sup>C]<b>8i</b> in non-human primates indicated that these three α-synuclein PET tracers penetrated the blood–brain barrier. Both [<sup>11</sup>C]<b>7f</b> and [<sup>18</sup>F]<b>7j</b> showed more favorable brain washout pharmacokinetics than [<sup>11</sup>C]<b>8i</b>. In vitro binding assays showed that [<sup>125</sup>I]<b>8i</b> is a very potent α-synuclein radioligand, with K<sub>d</sub> values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the <i>N</i>-(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting α-synuclein aggregates in vivo.https://www.mdpi.com/2073-4409/14/14/1108α-synuclein aggregatesParkinson’s diseaseradiolabelingPET imagingtracer development |
| spellingShingle | Haiyang Zhao Tianyu Huang Dhruva D. Dhavale Jennifer Y. O’Shea Zsofia Lengyel-Zhand Dinahlee Saturnino Guarino Jiwei Gu Xuyi Yue Ying-Hwey Nai Hao Jiang Marshall G. Lougee Vinayak V. Pagar Hee Jong Kim Benjamin A. Garcia E. James Petersson Chester A. Mathis Paul T. Kotzbauer Joel S. Perlmutter Robert H. Mach Zhude Tu Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography Cells α-synuclein aggregates Parkinson’s disease radiolabeling PET imaging tracer development |
| title | Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography |
| title_full | Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography |
| title_fullStr | Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography |
| title_full_unstemmed | Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography |
| title_short | Discovery of <i>N</i>-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography |
| title_sort | discovery of i n i 6 methoxypyridin 3 yl quinoline 2 amine derivatives for imaging aggregated α synuclein in parkinson s disease with positron emission tomography |
| topic | α-synuclein aggregates Parkinson’s disease radiolabeling PET imaging tracer development |
| url | https://www.mdpi.com/2073-4409/14/14/1108 |
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