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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| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/14/1108 |
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| Summary: | 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. |
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| ISSN: | 2073-4409 |