Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden.
Neurochem Int. 2011 Jan;58(1):60-8. doi: 10.1016/j.neuint.2010.10.013. Epub 2010 Nov 12.
In the human brain the monoaminooxidase-B enzyme or MAO-B is highly abundant in astrocytes. As astrocyte activity and, consequently, the activity of the MAO-B enzyme, is up-regulated in neuroinflammatory processes, radiolabelled analogues of deprenyl may serve as an imaging biomarker in neuroinflammation and neurodegeneration, including Alzheimer's disease. In the present study [(11)C]-L-deprenyl, the PET radioligand version of L-deprenyl or selegiline®, a selective irreversible MAO-B inhibitor was used in whole hemisphere autoradiographic experiments in human brain sections in order to test the radioligand's binding to the MAO-B enzyme in human brain tissue, with an eye on exploring the radioligand's applicability as a molecular imaging biomarker in human PET studies, with special regard to diagnostic detection of reactive astrogliosis. Whole hemisphere brain sections obtained from Alzheimer patients and from age matched control subjects were examined. In control brains the binding of [(11)C]-L-deprenyl was the highest in the hippocampus, in the basal ganglia, the thalamus, the substantia nigra, the corpus geniculatum laterale, the nucleus accumbens and the periventricular grey matter. In Alzheimer brains significantly higher binding was observed in the temporal lobes and the white matter. Furthermore, in the Alzheimer brains in the hippocampus, temporal lobe and white matter the binding negatively correlated with Braak stages. The highest binding was observed in Braak I-II, whereas it decreased with increasing Braak grades. The increased regional binding in Alzheimer brains coincided with the presence of an increased number of activated astrocytes, as demonstrated by correlative immunohistochemical studies with GFAP in adjacent brain slices. Deprenyl itself as well as the MAO-B antagonist rasagiline did effectively block the binding of the radioligand, whereas the MAO-A antagonist pirlindole did not affect it. Compounds with high affinity for the PBR system did not block the radioligand binding either, providing evidence for the specificity of [(11)C]-L-deprenyl for the MAO-B enzyme. In conclusion, the present observations indicate that [(11)C]-L-deprenyl may be a promising and selective imaging biomarker of increased MAO-B activity in the human brain and can therefore serve as a prospective PET tracer targeting neuroinflammation and neurodegeneration.
在人类大脑中，单胺氧化酶-B 酶或 MAO-B 在星形胶质细胞中高度丰富。由于星形胶质细胞活性，进而 MAO-B 酶的活性在神经炎症过程中被上调，因此 deprenyl 的放射性类似物可用作神经炎症和神经退行性变（包括阿尔茨海默病）的成像生物标志物。在本研究中，使用了 PET 放射性配体 [(11)C]-L-去甲替林，这是 L-去甲替林或司来吉兰的 PET 放射性配体版本，这是一种选择性不可逆的 MAO-B 抑制剂，用于人类大脑切片的整个半球放射自显影实验，以测试放射性配体与人类脑组织中 MAO-B 酶的结合情况，着眼于探索放射性配体作为人类 PET 研究中分子成像生物标志物的适用性，特别关注对反应性星形胶质增生的诊断检测。检查了从阿尔茨海默病患者和年龄匹配的对照组获得的整个半球脑切片。在对照组大脑中，[(11)C]-L-去甲替林的结合在海马体、基底神经节、丘脑、黑质、外侧膝状体、伏隔核和室周灰质中最高。在阿尔茨海默病大脑中，颞叶和白质的结合明显更高。此外，在阿尔茨海默病大脑的海马体、颞叶和白质中，结合与 Braak 分期呈负相关。在 Braak I-II 期观察到最高结合，而随着 Braak 等级的增加，结合逐渐降低。阿尔茨海默病大脑中区域结合的增加与激活星形胶质细胞数量的增加相吻合，这通过与相邻脑切片中的 GFAP 进行的相关免疫组织化学研究证明。去甲替林本身以及 MAO-B 拮抗剂雷沙吉兰有效地阻断了放射性配体的结合，而 MAO-A 拮抗剂吡咯烷则没有影响。对 PBR 系统具有高亲和力的化合物也没有阻断放射性配体的结合，这为 [(11)C]-L-去甲替林对 MAO-B 酶的特异性提供了证据。总之，目前的观察结果表明，[(11)C]-L-去甲替林可能是一种有前途的、选择性的成像生物标志物，可用于检测人类大脑中 MAO-B 活性的增加，因此可作为靶向神经炎症和神经退行性变的潜在 PET 示踪剂。
