PRECLINICAL AND CLINICAL PROPERTIES OF [123I]ABC577: A NOVEL RADIOIODINATED SPECT AGENT FOR IMAGING B-AMYLOID IN THE BRAIN
PRECLINICAL AND CLINICAL PROPERTIES OF [123I]ABC577: A NOVEL RADIOIODINATED SPECT AGENT FOR IMAGING B-AMYLOID IN THE BRAIN
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[123I]ABC577 的临床前和临床特性：一种用于大脑中 B 淀粉样蛋白成像的新型放射性碘化特异性试剂
DOI：
10.1016/j.jalz.2014.07.072
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Y. Shirakami
中科院分区：
文献类型：
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作者：
Y. Maya;Y. Okumura;Takako Onishi;Y. Shoyama;O. Barret;D. Alagille;D. Jennings;K. Marek;J. Seibyl;G. Tamagnan;A. Tanaka;Y. Shirakami
研究背景β-淀粉样蛋白（AAPs）是阿尔茨海默病（Alzheimer's disease，AD）的标志性疾病，其脑内的AAPs显像有助于AD的早期诊断和准确诊断。在过去的几年中，几种用于正电子发射断层扫描（PET）的AFDs显像剂已被美国食品和药物管理局批准，但仍然没有用于AD临床诊断的单光子发射计算机断层扫描（SPECT）试剂。由于SPECT在常规临床应用方面比PET更有用，因此SPECT放射性示踪剂的开发一直是一个关键问题。本研究的目的是评估一种新的放射性碘标记剂作为一个潜在的成像生物标志物，在brain. MethodsRadioiodinated咪唑并吡啶衍生物（[123 I] ABC 577）的设计和制备作为一种新的SPECT脑显像剂的候选。采用饱和结合试验和体外放射自显影法对[123 I] ABC 577与AD脑组织的结合进行了评价。此外，利用正常大鼠进行生物分布实验，以评价[123 I] ABC 577的生物学和辐射剂量学。此外，为了评估ABC 577的药理学特征，进行了各种受体和转运蛋白的结合测定。ABC 577的安全性也通过扩展的单次给药毒性研究进行了评价。我们进行了一项临床研究，以评估[123 I] ABC 577在human. ResultsNo载体添加放射性碘[123 I] ABC 577的有效性和安全性，成功地制备通过碘脱锡反应从相应的三丁基锡衍生物。在使用AD患者的脑匀浆的饱和结合测定中，[123 I] ABC 577显示出对A123的高结合亲和力（Kd= 1.83 nM）。[123 I] ABC 577在使用死后AD脑切片的放射自显影研究中清楚地证明了不仅特异性结合至Ablation，而且非常低的非特异性结合至白色物质。在使用正常大鼠的生物分布实验中，[123 I] ABC 577显示出高脑摄取（2分钟时为0.788% ID/g）和快速脑清除（60分钟时为0.044% ID/g）。[123 I] ABC 577的估计有效剂量与其他核医学试剂相似。在受体结合试验中，10 μmol/L浓度的ABC 577对多种受体和转运蛋白（如DA、5-HT、GABA、组胺）没有明显的抑制作用。扩展的单次给药毒性研究证明了ABC 577的安全性。在一项临床研究中，[123 I] ABC 577表现出良好的安全性和良好的能力，以区分AD患者从controls.ConclusionsPreliminary数据表明，[123 I] ABC 577可能是一个有用的SPECT成像工具，以确定在人脑中的腺苷酸。SPECT血管造影示踪剂的可用性可以增加AD成像诊断工具的可及性。
BackgroundThe imaging of ß-amyloid (Aß) in the brain, a hallmark of Alzheimer's disease (AD), may support the earlier and more accurate diagnosis of AD. In the past few years, several Aß imaging agents for positron emission tomography (PET) have been approved by the United States Food and Drug Administration, but there is still no single photon emission computed tomography (SPECT) agent for the clinical diagnosis of AD. Since SPECT is more useful than PET in terms of routine clinical use, the development of a SPECT radiotracer has been a critical issue. The aim of this research is to assess a novel radioiodinated agent as a potential imaging biomarker for Aß in brain.MethodsThe radioiodinated imidazopyridine derivative ([123I] ABC577) was designed and prepared as a candidate for novel SPECT Aß imaging agent. The binding of [123I] ABC577 to Aß was evaluated by saturation binding assay and in vitro autoradiography using postmortem AD brain tissues. In addition, the biodistribution experiments using normal rats were performed to evaluate the biokinetics and radiation dosimetry of [123I] ABC577. Furthermore, to assess the pharmacological profile of ABC577, the binding assays for various kinds of receptors and transporters were carried out. The safety of ABC577 was also evaluated by extended single-dose toxicity study. We performed a clinical study to assess the efficacy and safety of [123I] ABC577 in humans.ResultsNo-carrier-added radioiodinated [123I] ABC577 was successfully prepared through an iododestannylation reaction from the corresponding tributyltin derivative. In a saturation binding assay using brain homogenates of AD patients,[123I] ABC577 showed high binding affinity for Aß (Kd= 1.83 nM).[123I] ABC577 clearly demonstrated not only specific binding to Aß but also very low nonspecific binding to white matter in autoradiographic studies using postmortem AD brain sections. In biodistribution experiments using normal rats,[123I] ABC577 showed high brain uptake (0.788% ID/g at 2 min) and rapid clearance from the brain (0.044% ID/g at 60 min). The estimated effective doses of [123I] ABC577 were similar to those of other nuclear medicine agents. In receptor binding assays, no remarkable inhibition was observed for various receptors and transporters (eg, DA, 5-HT, GABA, Histamine) at 10 Âμmol/L concentrations of ABC577. Extended single-dose toxicity study demonstrated the safety of ABC577. In a clinical study,[123I] ABC577 demonstrated a favorable safety profile and a good ability to differentiate AD patients from controls.ConclusionsPreliminary data suggest that [123I] ABC577 may be a useful SPECT imaging tool to identify Aß in the human brain. The availability of a SPECT Aß tracer may provide increased accessibility to an imaging diagnostic tool for AD.