Institute of Psychiatry, De Crespigny Park, King's College London, London, United Kingdom.
J Nucl Med. 2013 Jan;54(1):139-44. doi: 10.2967/jnumed.112.108258. Epub 2012 Dec 5.
Changes in the density of imidazoline-I(2) binding sites have been observed in a range of neurologic disorders including Alzheimer's disease, Huntington's chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I(2) binding sites would further our understanding of the target and may find application as a biomarker for early disease diagnosis. Compound BU99008 has previously been identified as a promising I(2) ligand from autoradiography studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with (11)C in order to image the I(2) binding sites in vivo using PET.
(11)C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using (11)C-methyl iodide. A series of PET experiments was performed to investigate the binding of (11)C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I(2) ligand, BU224.
(11)C-BU99008 was obtained in good yield and specific activity. In vivo, (11)C-BU99008 displayed good brain penetration and gave a heterogeneous distribution with high uptake in the thalamus and low uptake in the cortex and cerebellum. (11)C-BU99008 brain kinetics were well described by the 1-tissue-compartment model, which was used to provide estimates for the total volume of distribution (V(T)) across brain regions of interest. Baseline V(T) values were ranked in the following order: thalamus > striatum > hippocampus > frontal cortex ≥ cerebellum, consistent with the known distribution and concentration of I(2) binding sites. Administration of a selective I(2) binding site ligand, BU224, reduced the V(T) to near-homogeneous levels in all brain regions.
(11)C-BU99008 appears to be a suitable PET radioligand for imaging the I(2) binding sites in vivo.
在一系列神经紊乱疾病中，包括阿尔茨海默病、亨廷顿舞蹈症和神经胶质瘤，都观察到咪唑啉-I（2）结合位点的密度发生了变化；然而，这些位点的确切功能仍不清楚。I（2）结合位点的 PET 探针将进一步加深我们对该靶点的理解，并可能作为早期疾病诊断的生物标志物得到应用。在放射自显影研究中，先前已经鉴定出 BU99008 是一种很有前途的 I（2）配体，对靶标具有高亲和力和良好的选择性。在这项研究中，用（11）C 对 BU99008 进行放射性标记，以便使用 PET 活体成像 I（2）结合位点。
用（11）C-甲基碘对去甲基前体进行 N-烷基化，对（11）C-BU99008 进行放射性标记。进行了一系列 PET 实验，以研究（11）C-BU99008 在猪脑中的结合情况，存在或不存在非放射性、竞争 I（2）配体 BU224 的情况下。
（11）C-BU99008 获得了良好的产率和比活度。在体内，（11）C-BU99008 具有良好的脑穿透性，表现出不均匀的分布，丘脑摄取高，皮质和小脑摄取低。（11）C-BU99008 的脑动力学通过 1 组织室模型很好地描述，该模型用于提供感兴趣脑区的总分布容积（V（T））的估计值。基线 V（T）值的排序如下：丘脑>纹状体>海马>额叶皮质≥小脑，与已知的 I（2）结合位点的分布和浓度一致。给予选择性 I（2）结合位点配体 BU224 后，所有脑区的 V（T）均降至近均匀水平。
（11）C-BU99008 似乎是一种适合用于活体成像 I（2）结合位点的 PET 放射性配体。
