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Background <p>Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in cerebral vessel walls, predominantly Aβ<sub>1−40</sub>, and frequently co-occurs with Alzheimer’s disease (AD). Reliable in vivo discrimination between vascular and parenchymal Aβ deposits (PEA) in AD is crucial for the assessment of CAA-related risks in anti-Aβ immunotherapies. Current Aβ PET tracers lack the ability to distinguish between vascular and parenchymal Aβ. The phenoxazine derivatives resorufin and ethyl-resorufin were previously shown to bind preferably to CAA over PEA. We therefore evaluated the fluorine-18-labeled resorufin derivative, [<sup>18</sup>F]fluoroethylresorufin ([<sup>18</sup>F]FER) as a potential PET tracer for selective in vivo detection of vascular Aβ.</p> Results <p>The binding specificity of [<sup>3</sup>H]FER was assessed using recombinant Aβ<sub>1−40</sub> and Aβ<sub>1−42</sub> fibrils as well as in vitro autoradiography on mouse brain tissue of APP23 (CAA+/PEA+) and APPPS1 (CAA-/PEA+) models, and compared to those of [<sup>3</sup>H]PIB. [<sup>18</sup>F]FER and its deuterated analog were synthesized for evaluation of brain pharmacokinetics, metabolism, and in vivo binding using PET imaging in wild-type, APPPS1, and APP23 mice. [<sup>3</sup>H]FER bound with higher affinity to Aβ<sub>1−40</sub> (K<sub>d</sub> = 9.4 nM) than to Aβ<sub>1−42</sub> (K<sub>d</sub> = 89.1 nM), consistent with its intended CAA selectivity. Autoradiography revealed preferential labeling of vascular amyloid in APP23 mice, with minimal binding in APPPS1 and wild-type tissue. In vivo, [<sup>18</sup>F]FER exhibited high brain uptake (peak SUV = 1.5) and rapid clearance, but metabolic degradation was fast, with ~ 45% parent fraction remaining in the brain at 15&#xa0;min. Deuteration did not improve stability but did improve washout kinetics. PET imaging with (d<sub>4</sub>)-[<sup>18</sup>F]FER demonstrated a cortical uptake pattern similar to [<sup>11</sup>C]PIB, indicating non-selective binding in vivo.</p> Conclusions <p>[<sup>18</sup>F]FER showed promising in vitro affinity for vascular amyloid but lacked in vivo selectivity, likely due to rapid metabolism and high lipophilicity. These findings highlight the challenges of achieving in vivo CAA specificity and provide guidance for the optimization of future tracers targeting vascular Aβ pathology.</p>

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Preclinical evaluation of [18F]fluoroethylresorufin as PET tracer for cerebral amyloid angiopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月16日

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  • Daniel Bleher,
  • Marilena Poxleitner,
  • Ann-Kathrin Grotegerd,
  • Oliver Hihn,
  • Laura Kuebler,
  • Gregory Bowden,
  • Martin Schaller,
  • Florian C. Maier,
  • Bettina Weigelin,
  • Bernd J. Pichler,
  • Andreas Maurer,
  • Kristina Herfert

摘要

Background

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in cerebral vessel walls, predominantly Aβ1−40, and frequently co-occurs with Alzheimer’s disease (AD). Reliable in vivo discrimination between vascular and parenchymal Aβ deposits (PEA) in AD is crucial for the assessment of CAA-related risks in anti-Aβ immunotherapies. Current Aβ PET tracers lack the ability to distinguish between vascular and parenchymal Aβ. The phenoxazine derivatives resorufin and ethyl-resorufin were previously shown to bind preferably to CAA over PEA. We therefore evaluated the fluorine-18-labeled resorufin derivative, [18F]fluoroethylresorufin ([18F]FER) as a potential PET tracer for selective in vivo detection of vascular Aβ.

Results

The binding specificity of [3H]FER was assessed using recombinant Aβ1−40 and Aβ1−42 fibrils as well as in vitro autoradiography on mouse brain tissue of APP23 (CAA+/PEA+) and APPPS1 (CAA-/PEA+) models, and compared to those of [3H]PIB. [18F]FER and its deuterated analog were synthesized for evaluation of brain pharmacokinetics, metabolism, and in vivo binding using PET imaging in wild-type, APPPS1, and APP23 mice. [3H]FER bound with higher affinity to Aβ1−40 (Kd = 9.4 nM) than to Aβ1−42 (Kd = 89.1 nM), consistent with its intended CAA selectivity. Autoradiography revealed preferential labeling of vascular amyloid in APP23 mice, with minimal binding in APPPS1 and wild-type tissue. In vivo, [18F]FER exhibited high brain uptake (peak SUV = 1.5) and rapid clearance, but metabolic degradation was fast, with ~ 45% parent fraction remaining in the brain at 15 min. Deuteration did not improve stability but did improve washout kinetics. PET imaging with (d4)-[18F]FER demonstrated a cortical uptake pattern similar to [11C]PIB, indicating non-selective binding in vivo.

Conclusions

[18F]FER showed promising in vitro affinity for vascular amyloid but lacked in vivo selectivity, likely due to rapid metabolism and high lipophilicity. These findings highlight the challenges of achieving in vivo CAA specificity and provide guidance for the optimization of future tracers targeting vascular Aβ pathology.