Liver Specific Manganese Based MRI Contrast Agent

项目概要/摘要 肝细胞癌（HCC）是世界范围内癌症死亡的第二大常见原因， 死亡率的增长速度比任何其他癌症都要快。转移性肝病的发生率更高， 其发病率高于HCC，并且与高死亡率相关。有一个显著的生存益处 与肝脏肿瘤的早期检测有关。然而，基于肝脏特异性钆（Gd）的MRI造影剂 作为诊断肝脏恶性肿瘤的放射学护理标准的药物（GBCA） 满足临床需求，并受到严格的监管审查，担心Gd保留和延迟 Gd相关毒性。用于肝脏成像的两种GBCA，Gd-EOB-DTPA和Gd-BOPTA，属于 由无环螯合剂组成的GBCA类，与Gd释放的最高风险相关。的 欧洲药品管理局暂停了3种无环细胞外液GBCA的上市许可， 但允许用于肝脏特异性成像的GBCA在肝脏扫描中限制使用， 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提供富血管结构的初始动态相增强，随后累积 通过有机阴离子转运蛋白肽（OATP）的作用在肝细胞中产生肝细胞 延迟相位成像增强。在动态和动态过程中观察到的病变中的不同对比 延迟相位成像使得能够对肝脏恶性肿瘤与常见的良性异常进行鉴别诊断。 然而，Gd-EOB-DTPA对延迟期病变的动态增强效果不如Gd- 但Gd-BOPTA的延迟期增强低于Gd-EOB- DTPA， 在注射后1小时进行，限制了患者吞吐量。我们解决这些问题的办法是开发一个Gd- 具有优化的动态和延迟相位对比特性的游离肝脏特异性造影剂。揭示 制药公司已经证明，细胞外锰（Mn）基造影剂RVP-001（又名 Mn-PyC 3A）提供与GBCA相当的细胞外对比度，不释放游离Mn 2+离子，并且更 比GBCA更有效地从体内消除。在这个FastTrack应用程序中，我们将开发面向OATP的 利用化学稳定的高弛豫率Mn-PyC 3A核心进行肝脏特异性成像的造影剂。在 第一阶段，我们将确定一个主要的候选人，并证明强，明显的增强肝脏肿瘤， 人源化OATP敲入小鼠。在第二阶段，我们将进行铅优化方面的弛豫， 药代动力学、安全性和肝脏图像对比度，并选择最终临床应用的开发候选者（DC） 翻译.我们将在大鼠和兔肝癌模型中验证我们的DC，并评估其在大鼠中的安全性。我们 将开发一种可扩展的、具有成本效益的DC合成方法，用于向cGMP生产商进行技术转让。

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.