Tc-99m PIB Analogs for Imaging ??-Amyloid Deposition with SPECT

用于通过 SPECT 成像 ??-淀粉样蛋白沉积的 Tc-99m PIB 类似物

• 批准号: 7938874
• 负责人: NEALE S MASON
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938874
• 关键词: Affinity; Alzheimer' s Disease; Amyloid; Amyloid deposition; Autoradiography; Binding; Brain; Clinical; Data; Dementia; Deposition; Development; Diagnostic; Discipline of Nuclear Medicine; Early Diagnosis; Early treatment; Effectiveness; Elderly; Goals; Hand; Hospitals; Human; Image; Individual; Label; Life; Measures; Metabolic Clearance Rate; Minority; Mus; Pathogenesis; Patients; Pittsburgh Compound-B; Positron-Emission Tomography; Radioisotopes; Research; Slice; Structure-Activity Relationship; System; Technetium 99m; Tracer; Translating; amyloid imaging; amyloid peptide; analog; base; clinical application; cost; design; imaging modality; lipophilicity; molecular size; pre-clinical; radiotracer; single photon emission computed tomography; stable isotope

Alzheimer?s disease (AD) is the most common cause of dementia in the elderly. The pathogenesis of AD is unclear but involves the formation of aggregated a-amyloid peptides (Aa) in the brain. Research on antiamyloid therapy has shown potential to treat AD, and the development of anti-amyloid therapies may be facilitated by the use of 2-arylbenzothiazole amyloid imaging agents such as Pittsburgh Compound-B (PIB). Once therapies are in hand, tracers such as PIB could be even more useful for identifying preclinical cases of AD as candidates for early intervention and to follow the effectiveness of therapy in individual patients. Unfortunately, the 11C label on PIB limits its use to highly sophisticated academic PET (positron emission tomography) facilities (< 10 % of all PET facilities). 18F derivatives of PIB have recently been developed and could increase the availability of amyloid imaging to all PET facilities, but this still represents a minority of modern hospitals, as only a small fraction of hospitals have a PET scanner. However, many more hospitals have the capacity to perform single photon emission computed tomography (SPECT). Our long-term goal is to develop an Aa radiotracer which can be prepared easily at minimal cost, and has widespread clinical applicability via the use of the convenient and cost-effective imaging modality, SPECT. In this proposed research, we will investigate the potential of 99mTc-labeled 2-arylbenzothiazoles as Aa imaging agents. 99mTc is an inexpensive and readily available diagnostic radioisotope. Many 2- arylbenzothiazole derivatives have high binding affinity to aggregated Aa. 99mTc-labeled derivatives of 2- arylbenzothiazole may be ideal radiotracers for imaging Aa burden with SPECT. Since there is no stable isotope of Tc available, we will use Re, a congener of Tc, as a surrogate. First we will design and synthesize compact, neutral and lipophilic Re-containing derivatives of 2-arylbenzothiazole with high binding affinity to aggregated Aa. Complexation of 2-arylbenzothiazoles with Re will be achieved via the use of an integrated chelating system to minimize the overall molecular size. We will evaluate the potential of Recontaining derivatives of 2-arylbenzothiazole based on their lipophilicity and binding affinity to aggregated Aa. We will then translate promising Re-containing derivatives of 2-arylbenzothiazole into promising 99mTclabeled 2-arylbenzothiazoles, and assess the suitability of these 99mTc analogs for clinical imaging by determining brain entry and clearance in mice. The data generated by this proposed research will provide us invaluable structure-activity relationship information for the development of 99mTc-labeled Aa imaging agents which could be used for early diagnosis of Alzheimer?s disease and facilitating the development and application of anti-amyloid therapy. Project

老年痴呆症？阿尔茨海默病（AD）是老年痴呆症最常见的原因。AD的发病机制是 不清楚，但涉及脑中聚集的α-淀粉样肽（Aa）的形成。抗淀粉样蛋白的研究 治疗已显示出治疗AD的潜力，抗淀粉样蛋白治疗的发展可能是 通过使用2-芳基苯并噻唑淀粉样蛋白成像剂如匹兹堡化合物-B（PIB）来促进。 一旦疗法在手，PIB等示踪剂可能对识别临床前病例更有用 作为早期干预的候选人，并在个别患者中跟踪治疗的有效性。 不幸的是，PIB上的11 C标签限制了其在高度复杂的学术PET（正电子发射）中的使用 断层扫描）设施（<所有PET设施的10%）。最近已经开发了PIB的18F衍生物， 可以增加淀粉样蛋白成像对所有PET设施的可用性，但这仍然代表了少数 现代医院，因为只有一小部分医院有PET扫描仪。然而，更多的医院 具有进行单光子发射计算机断层扫描（SPECT）的能力。我们的长期目标是 开发一种Aa放射性示踪剂，其可以以最小的成本容易地制备，并且具有广泛的临床应用。 通过使用方便且具有成本效益的成像模式SPECT， 在这项研究中，我们将研究99 mTc标记的2-芳基苯并噻唑作为Aa的潜力， 显像剂99 mTc是一种廉价且容易获得的诊断放射性同位素。许多2- 芳基苯并噻唑衍生物对聚集的Aa具有高的结合亲和力。99 mTc标记的2- 芳基苯并噻唑可能是SPECT显像Aa负荷的理想示踪剂。由于没有稳定的 如果没有Tc的同位素，我们将使用Tc的同系物Re作为替代物。首先，我们将设计和 合成致密、中性、亲脂性高结合2-芳基苯并噻唑含稀土衍生物 对聚集的Aa的亲和力。2-芳基苯并噻唑与Re的络合将通过使用 整合的螯合系统，以最大限度地减少整体分子大小。我们将评估重新获得 2-芳基苯并噻唑衍生物的亲脂性和对聚集体的结合亲和力 AA.然后，我们将有前途的2-芳基苯并噻唑的含Re衍生物转化为有前途的99 mTclabled 2-芳基苯并噻唑，并评估这些99 mTc类似物的临床成像的适用性， 测定小鼠的脑进入和清除。这项拟议研究产生的数据将提供 为开发99 mTc标记的Aa成像提供了宝贵的构效关系信息 哪些药物可用于早期诊断阿尔茨海默病？的疾病和促进发展， 抗淀粉样蛋白治疗的应用。 项目

项目成果

Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents.

• DOI: 10.1016/j.bmcl.2013.01.068
• 发表时间: 2013-03-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Pan, Jinhe;Mason, Neale S.;Debnath, Manik L.;Mathis, Chester A.;Klunk, William E.;Lin, Kuo-Shyan
• 通讯作者: Lin, Kuo-Shyan