Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
Department of Psychiatry, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan.
Eur J Nucl Med Mol Imaging. 2021 Aug;48(9):2846-2855. doi: 10.1007/s00259-021-05235-0. Epub 2021 Feb 10.
Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains.
Seven healthy males underwent a 90-min PET scan after injection of C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (Vs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTM) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference.
PET images with C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. V values were robustly estimated by two-tissue compartment model analysis (mean V = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTM and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTM and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of C-MTP38-PET.
We have provided the first demonstration of PET visualization of PDE7 in human brains. C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.
磷酸二酯酶 7（PDE7）是一种选择性水解环腺苷酸单磷酸的酶，其功能障碍与神经精神疾病有关。然而，迄今为止，还无法在人类大脑中对 PDE7 进行体内可视化。我们使用最近开发的新型 PET 配体 C-MTP38，旨在对活人大脑的 PDE7 进行成像和定量。
7 名健康男性在注射 C-MTP38 后接受了 90 分钟的 PET 扫描。我们对 6 名受试者进行了动脉采血和血浆代谢物分析，以获得代谢校正的输入函数。使用房室模型、Logan 图和池田多线性分析（MA1）估计区域总分布容积（Vs）。我们进一步使用原始多线性参考组织模型（MRTM）和标准化摄取值比（SUVR）方法，以小脑皮质为参考，对特异性放射性配体结合进行定量。
C-MTP38 的 PET 图像显示，在包括纹状体、苍白球和丘脑在内的多个脑区有较高的保留，而小脑皮质的清除较快，与 PDE7 的已知分布一致。两室模型分析（苍白球的平均 V 值为 4.2）、Logan 图和 MA1 均能稳健地估计 V 值，且彼此之间非常吻合，表明 C-MTP38 结合是可逆的。此外，间接法和 MRTM 及 SUVR 法估计的结合值之间有很好的一致性，表明这些方法可用于 PDE7 的可靠定量。由于 MRTM 和 SUVR 不需要动脉采血，因此对于 C-MTP38-PET 的临床应用最实用。
我们首次在人类大脑中展示了 PDE7 的 PET 可视化。C-MTP38 是一种有前途的新型 PET 配体，可用于定量研究中枢 PDE7。
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