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Purpose <p>Dopamine transporter (DAT) in the central nervous system is an attractive biomarker for the diagnosis and study of various neurodegenerative diseases. To develop <i>in vivo</i> metabolically&#xa0;stable positron emission tomography (PET) probes for DAT imaging with a high target/background ratio, two <sup>18</sup>F-labeled tropane derivatives with deuteration on both the <i>N</i>-fluoropropyl and 2<i>β</i>-carbomethoxy groups of the tropane scaffold were synthesized and evaluated.</p> Methods <p>Radioligands [<sup>18</sup>F]<b>6</b> and [<sup>18</sup>F]<b>10</b> were synthesized from anhydroecgonine and radiolabeled with <sup>18</sup>F through a "two-step one-pot" method. Lipophilicity, <i>in vitro</i> binding assay and microPET imaging in rats were performed. [<sup>18</sup>F]<b>10</b> showed a higher standardized uptake value ratio (SUVr) and was selected for further evaluations by <i>in vivo</i> metabolism and biodistribution.</p> Results <p>The radioligands [<sup>18</sup>F]<b>6</b> and [<sup>18</sup>F]<b>10</b> were obtained in radiochemical purities &gt; 98% and molar activity of about 30&#xa0;GBq/μmol. [<sup>18</sup>F]<b>6</b> or [<sup>18</sup>F]<b>10</b> demonstrated high specificity and binding affinity to DAT <i>in vitro</i>, with IC<sub>50</sub> values between 2 ~ 3&#xa0;nM. MicroPET imaging in wild type Sprague–Dawley rats revealed that [<sup>18</sup>F]<b>10</b> has a higher SUVr than [<sup>18</sup>F]<b>6</b>. Blocking experiments demonstrated the selectivity and reversibility of [<sup>18</sup>F]<b>10</b> for DAT binding in microPET imaging. The diagnostic efficacy of [<sup>18</sup>F]<b>10</b> for DAT-related disorders was verified in semi-PD model rats with microPET. <i>In vivo</i> metabolic studies in rats indicated that [<sup>18</sup>F]<b>10</b> exhibited enhanced stability. Biodistribution experiments further confirmed that [<sup>18</sup>F]<b>10</b> accumulated in the DAT-rich region of the striatum.</p> Conclusion <p>[<sup>18</sup>F]<b>10</b> is a highly promising metabolically stable <sup>18</sup>F-labeled PET probe for DAT imaging, with potential clinical applications in detecting and monitoring DAT-related neurological disorders.</p>

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Development of 18F-Labeled Deuterated Tropane Derivatives with High Metabolic Stability for PET Imaging of the Dopamine Transporter

  • 期刊论文

  • 发表日期：

    2025年5月14日

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  • Jingjing Hong,
  • Jing Kang,
  • Jiaojiao Zuo,
  • Yi Fang,
  • Chunyi Liu,
  • Jingwen Li,
  • Zhengping Chen

摘要

Purpose

Dopamine transporter (DAT) in the central nervous system is an attractive biomarker for the diagnosis and study of various neurodegenerative diseases. To develop in vivo metabolically stable positron emission tomography (PET) probes for DAT imaging with a high target/background ratio, two 18F-labeled tropane derivatives with deuteration on both the N-fluoropropyl and 2β-carbomethoxy groups of the tropane scaffold were synthesized and evaluated.

Methods

Radioligands [18F]6 and [18F]10 were synthesized from anhydroecgonine and radiolabeled with 18F through a "two-step one-pot" method. Lipophilicity, in vitro binding assay and microPET imaging in rats were performed. [18F]10 showed a higher standardized uptake value ratio (SUVr) and was selected for further evaluations by in vivo metabolism and biodistribution.

Results

The radioligands [18F]6 and [18F]10 were obtained in radiochemical purities > 98% and molar activity of about 30 GBq/μmol. [18F]6 or [18F]10 demonstrated high specificity and binding affinity to DAT in vitro, with IC50 values between 2 ~ 3 nM. MicroPET imaging in wild type Sprague–Dawley rats revealed that [18F]10 has a higher SUVr than [18F]6. Blocking experiments demonstrated the selectivity and reversibility of [18F]10 for DAT binding in microPET imaging. The diagnostic efficacy of [18F]10 for DAT-related disorders was verified in semi-PD model rats with microPET. In vivo metabolic studies in rats indicated that [18F]10 exhibited enhanced stability. Biodistribution experiments further confirmed that [18F]10 accumulated in the DAT-rich region of the striatum.

Conclusion

[18F]10 is a highly promising metabolically stable 18F-labeled PET probe for DAT imaging, with potential clinical applications in detecting and monitoring DAT-related neurological disorders.