First-in-human study of D6-[18F]FP-(+)-DTBZ, a novel VMAT2 tracer: whole-body biodistribution and brain PET comparison with [18F]FP-(+)-DTBZ (AV-133)

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR EJNMMI Radiopharmacy and Chemistry Pub Date : 2024-10-16 DOI:10.1186/s41181-024-00301-y

Ruiyue Zhao, Jinhua Chen, Ting Ye, Jianmin Chu, Jingwen Li, Yan Zhang, Siran Xu, Shaoyu Liu, Ling Chen, Karl Ploessl, David Alexoff, Hank F. Kung, Lin Zhu, Xinlu Wang

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Abstract

Background

In the central nervous system, type 2 vesicular monoamine transporters (VMAT2) are responsible for the reuptake of monoamines from synaptic junction back to pre-synaptic terminal vesicles. These transporters are functionally crucial as they reflect the integrity of monoamine neurons. D6-[¹⁸F]FP-(+)-DTBZ, a novel deuterated VMAT2 radioligand, has shown promise as a potential PET tracer for the diagnosis of Parkinson’s disease (PD). This study evaluates the biodistribution and dosimetry of D6-[¹⁸F]FP-(+)-DTBZ and includes a head-to-head comparison with its non-deuterated version, [¹⁸F]FP-(+)-DTBZ (AV-133), in healthy individuals and PD patients.

Results

The automated synthesis of D6-[¹⁸F]FP-(+)-DTBZ using the SPE method was accomplished in 35 min, yielding a high radiochemical purity (> 99%) and high radiochemical yields (35 ± 5%). The biodistribution and dosimetry study indicated an effective dose of 37.1 ± 7.2 μSv/MBq, with the liver receiving the highest radiation dose (289.6 ± 42.1 μGy/MBq), followed by pancreas (185.2 ± 29.1 μGy/MBq). Brain imaging with D6-[¹⁸F]FP-(+)-DTBZ exhibited a significantly increased uptake in VMAT2-rich regions, particularly the striatum. In a head-to-head comparison between [¹⁸F]FP-(+)-DTBZ and D6-[¹⁸F]FP-(+)-DTBZ, the latter exhibited approximately 15% higher SUVR in the caudate, putamen, and nucleus accumbens. Preliminary studies in PD patients showed a substantial reduction in VMAT2 uptake in the striatum, with the most pronounced decrease observed in the putamen (a 53% decline).

Conclusions

D6-[¹⁸F]FP-(+)-DTBZ is a safe and improved VMAT2-specific imaging agent, which may be suitable for diagnosing PD by evaluating changes in VMAT2 binding of monoamine neurons in the brain.

Trial registration Chinese Clinical Trial Registry, ChiCTR2200057218, Registered 16 August 2021, https://www.chictr.org.cn/bin/project/edit?pid=142725.

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新型 VMAT2 示踪剂 D6-[18F]FP-(+)-DTBZ 的首次人体研究：全身生物分布和脑 PET 与 [18F]FP-(+)-DTBZ (AV-133) 的比较

背景在中枢神经系统中，2 型囊泡单胺转运体（VMAT2）负责将单胺从突触接头重新吸收回突触前末端囊泡。这些转运体在功能上至关重要，因为它们反映了单胺神经元的完整性。D6-[18F]FP-(+)-DTBZ是一种新型的氚代VMAT2放射性配体，已被证明有望成为诊断帕金森病（PD）的潜在PET示踪剂。本研究评估了D6-[18F]FP-(+)-DTBZ在健康人和帕金森病患者中的生物分布和剂量测定，并将其与非氘化型[18F]FP-(+)-DTBZ（AV-133）进行了头对头比较。结果采用SPE方法在35分钟内完成了D6-[18F]FP-(+)-DTBZ的自动合成，获得了高放射化学纯度（99%）和高放射化学收率（35 ± 5%）。生物分布和剂量学研究表明，有效剂量为 37.1 ± 7.2 μSv/MBq，肝脏接受的辐射剂量最高（289.6 ± 42.1 μGy/MBq），其次是胰腺（185.2 ± 29.1 μGy/MBq）。用D6-[18F]FP-(+)-DTBZ进行的脑成像显示，富含VMAT2的区域，尤其是纹状体，摄取量明显增加。在对[18F]FP-(+)-DTBZ和D6-[18F]FP-(+)-DTBZ进行头对头比较时，后者在尾状核、普坦门和伏隔核的SUVR高出约15%。结论D6-[18F]FP-(+)-DTBZ是一种安全、改良的VMAT2特异性成像剂，可通过评估脑内单胺神经元的VMAT2结合变化诊断PD。

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