Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
J Alzheimers Dis. 2018;61(3):1241-1252. doi: 10.3233/JAD-170115.
Early detection of Alzheimer's disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes.
To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates.
The targeted CA consisted of an HIV-1 Tat cell penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n = 5-8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake.
The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls.
Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent.
阿尔茨海默病（AD）病理的早期检测对诊断和临床试验都是一个严峻的挑战。天冬氨酸蛋白酶 Cathepsin D（CatD）在 AD 中过度表达，可能是疾病的生物标志物。我们之前设计了一种独特的对比剂（CA），用于双重光学和磁共振成像 CatD 类酶的活性。
比较新型、更敏感且更适合临床转化的靶向 CatD 活性的 68Ga PET 示踪剂在 5XFAD 小鼠和非 Tg 同窝仔鼠中的摄取和保留。
靶向 CA 由 HIV-1 Tat 细胞穿透肽（CPP）与专门针对天冬氨酸半胱氨酸蛋白酶的靶向切割序列以及 DOTA 缀合物螯合 68Ga 组成。在静脉注射 CA 后，使用西门子 Inveon 小动物 microPET 在雌性 Tg AD 小鼠和非 Tg 年龄匹配的雌性同窝仔鼠（n=5-8）中采集 PET 图像，在 2、6 和 9 个月时进行。此外，在 10 个月时进行 18F 氟脱氧葡萄糖（FDG）PET 成像以测量葡萄糖摄取。
Tg 小鼠在所有年龄段的前脑与后脑相比，靶向 CA 的相对摄取率明显更高，与组织学一致。相比之下，在其他器官中未观察到 CA 摄取的差异。此外，与年龄匹配的非 Tg 对照相比，Tg 小鼠在 10 个月时前脑与后脑的 FDG 相对摄取率没有差异。
使用新型靶向 PET 对比剂在 AD 的 5XFAD 小鼠模型中体内检测到天冬氨酸半胱氨酸酶活性升高。
