Liver Specific Manganese Based MRI Contrast Agent

项目摘要/摘要 肝细胞癌是全球第二大癌症死亡原因。 死亡率的增长速度比其他任何癌症都要快。转移性肝病发生时 其发病率高于肝细胞癌，也与高死亡率有关。对生存有很大的好处 与肝脏肿瘤的早期发现有关。然而，基于肝脏特异性Gd(Gd)的MRI对比剂 作为诊断肝脏恶性肿瘤的放射学标准的试剂(GBCA)并不是最理想的 满足临床需求，并因担心Gd滞留和延迟而受到严格的监管审查 Gd相关毒性。用于肝脏成像的两种GBCA，Gd-EOB-DTPA和Gd-BOPTA属于 由非环络合剂组成的一类GBCA，它们与Gd释放的风险最高有关。这个 欧洲药品管理局暂停了3种非环胞外液GBCA的上市许可， 但允许用于肝脏特异性成像的GBCA在肝脏扫描中仍可有限使用，因为 这些试剂满足了肝癌和转移性肝病诊断的需要。Gd-EOB-DTPA和Gd- BOPTA提供了多血管结构的初始动态增强，并随后积累 在肝细胞中通过有机阴离子转运肽(OATPs)的作用导致肝细胞 延迟相位成像的增强。动态和动态观察病变的不同对比 延迟时相成像可使肝脏恶性肿瘤与常见的良性异常鉴别诊断。 然而，与Gd-EOB-DTPA相比，Gd-EOB-DTPA对延迟相病变的动态增强效果较差。 BOPTA，但Gd-BOPTA的延迟相增强小于Gd-EOB-DTPA和IS 在注射后1小时执行，限制了患者的吞吐量。我们对这些问题的解决方案是开发一种Gd- 具有优化的动态和延迟相位对比剂的游离肝脏特异性造影剂。揭示 制药公司已经证明，基于细胞外锰(Mn)的造影剂RVP-001(又名 Mn-PyC3A)提供与GBCA相当的细胞外对比度，不释放游离Mn2+，而且 比GBCA更能有效地从体内消除。在此FastTrack应用程序中，我们将开发以OATP为目标的 利用化学稳定性、高弛豫度的Mn-PyC3A核心进行肝脏特异性成像的造影剂。在……里面 第一阶段，我们将确定一个主要候选者，并在以下几个阶段展示肝肿瘤的显著增强 人源化OATP基因敲除小鼠。在第二阶段，我们将执行关于松弛程度的引线优化， 药物动力学、安全性和肝脏影像对比，并为最终临床选择开发候选药物(DC) 翻译。我们将在大鼠和兔肝癌模型上验证我们的DC，并在大鼠身上评估其安全性。我们 将开发一种可扩展的、具有成本效益的DC合成，用于向cGMP制造商转让技术。

Project Summary / Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide and HCC mortality is increasing at a faster rate than any other cancer. Metastatic liver disease occurs with greater frequency than HCC and is also associated with high mortality rates. There is a significant survival benefit associated with early detection of liver tumors. However, the liver-specific gadolinium (Gd)-based MRI contrast agents (GBCAs) which are the radiologic standard of care for diagnoses of liver malignances do not optimally meet clinical needs and have come under intense regulatory scrutiny over concerns of Gd retention and delayed Gd-associated toxicity. The two GBCAs used for liver imaging, Gd-EOB-DTPA and Gd-BOPTA, belong to the class of GBCAs comprised of acyclic chelators, which are associated with the highest risk of Gd release. The European Medicines Agency suspended the marketing authorizations for the 3 acyclic extracellular fluid GBCAs, but allowed the GBCAs used for liver specific imaging to remain available for restricted use in liver scans because these agents satisfy the need for diagnosis of liver cancer and metastatic liver disease. Gd-EOB-DTPA and Gd- BOPTA provide initial dynamic phase enhancement of hypervascular structures, and subsequently accumulate in hepatocytes via the action of organic anion transporter peptides (OATPs) resulting in hepatocellular enhancement on delayed phase imaging. The different contrasts observed in lesions during dynamic and delayed phase imaging enable differential diagnosis of liver malignancies from common, benign abnormalities. However, the dynamic enhancement of delayed phase lesions is poor with Gd-EOB-DTPA compared to Gd- BOPTA, but the delayed phase enhancement with Gd-BOPTA is lower than with Gd-EOB- DTPA and is performed 1 hour post injection, limiting patient throughput. Our solution to these problems is to develop a Gd- free liver-specific contrast agent with optimized dynamic and delayed phase contrast properties. Reveal Pharmaceuticals has demonstrated that the extracellular manganese (Mn)-based contrast agent RVP-001 (aka Mn-PyC3A) provides equivalent extracellular contrast to GBCAs, does not release free Mn2+ ion, and is more effectively eliminated from the body than GBCAs. In this FastTrack application we will develop OATP-targeted contrast agents that utilize the chemically stable, high relaxivity Mn-PyC3A core for liver specific imaging. In Phase I we will identify a lead candidate and demonstrate strong, conspicuous enhancement of liver tumors in humanized OATP knock-in mice. In Phase II we will perform lead optimization with respect to relaxivity, pharmacokinetics, safety, and liver image contrast, and select a development candidate (DC) for ultimate clinical translation. We will validate our DC in rat and rabbit models of liver cancer, and evaluate its safety in rats. We will develop a scalable, cost effective synthesis of the DC for technology transfer to a cGMP manufacturer.