Liver Specific Manganese Based MRI Contrast Agent

肝脏专用锰基 MRI 造影剂

• 批准号: 10247834
• 负责人: Vera Hoffman
• 金额: $ 99.93万
• 依托单位: REVEAL PHARMA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-08 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247834
• 关键词: Address; Authorization documentation; Benign; Binding Proteins; Biological Assay; Blood; Breast; Cancer Etiology; Cancer Model; Cardiotoxicity; Cells; Cessation of life; Chelating Agents; Chemicals; Chromatography; Clinical; Colorectal; Complex; Contrast Media; Cyclic GMP; Development; Diagnosis; Diethylnitrosamine; Differential Diagnosis; Disease; Dose; Drug Kinetics; Early Diagnosis; Elements; European; Extracellular Fluid; Focal Nodular Hyperplasia; Frequencies; Gadolinium; Gadolinium DTPA; General Hospitals; Gold; Hepatocyte; Histologic; Hour; Human; Human body; Hypervascular; Image; Immune; In Vitro; Injections; Ions; Knock-in Mouse; Lesion; Libraries; Liver; Liver diseases; Liver neoplasms; Liver parenchyma; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Manganese; Manufacturer Name; Marketing; Massachusetts; Maximum Tolerated Dose; Measures; Medicine; Metabolism; Metastatic Neoplasm to the Liver; Microsomes; Modeling; Neoplasm Metastasis; Noise; Nutritional; Organic Anion Transporters; Oryctolagus cuniculus; Patients; Pentetic Acid; Peptides; Pharmacologic Substance; Phase; Plasma Proteins; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Property; Protocols documentation; Radiology Specialty; Rattus; Reaction; Rifampin; Safety; Screening for Hepatocellular Cancer; Series; Structure; Structure-Activity Relationship; Technology; Technology Transfer; Toxic effect; Toxicokinetics; base; candidate selection; clinical translation; contrast imaging; cost effective; extracellular; genotoxicity; high risk; in vivo; lead candidate; lead optimization; lipophilicity; liver imaging; melanoma; mortality; preclinical development; standard of care; toxic metal; tumor; uptake

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.

项目摘要 /摘要 肝细胞癌（HCC）是全球癌症死亡和HCC的第二大最常见原因 与任何其他癌症相比，死亡率的增长速度更快。转移性肝病发生更大 频率比HCC，也与高死亡率有关。有很大的生存益处 与早期发现肝肿瘤有关。但是，肝特异性gadolinium（GD）的MRI对比度 代理（GBCA）是诊断肝脏恶性肿瘤的放射护理标准 满足临床需求，并对GD保留的担忧进行了严格的监管审查 GD相关的毒性。用于肝脏成像的两个GBCA，GD-EOB-DTPA和GD-BOPTA，属于 由无环螯合剂组成的GBCA类，与GD释放的风险最高有关。这 欧洲药品局暂停了3个无环的细胞外液体GBCA的营销授权， 但允许用于肝脏特定成像的GBCA仍然可用于肝脏扫描中的限制使用 这些药物满足诊断肝癌和转移性肝病的必要性。 GD-EOB-DTPA和GD- BOPTA提供了高血管结构的初始动态相，然后积累 通过有机阴离子转运蛋白肽（OATP）的作用在肝细胞中，导致肝细胞 增强延迟相成像。动态和 延迟的相成像使肝脏恶性肿瘤的差异诊断能够从常见的良性异常中进行。 但是，与GD-相比 bopta，但与gd-bopta相比，延迟相位的相位比gd-eobdtpa低，并且 注射后进行1小时，限制患者吞吐量。我们解决这些问题的方法是开发GD- 具有优化的动态和延迟相对比特性的游离肝特异性对比剂。揭示 药品表明，基于细胞外锰（MN）的对比剂RVP-001（又名） Mn-pyc3a）提供与GBCA的等效细胞外对比，不释放自由MN2+离子，并且更多 有效地从身体中消除了比GBCA。在此FastTrack应用程序中，我们将开发目标 利用化学稳定的高松弛度Mn-Pyc3a核心的对比剂进行肝脏特异性成像。在 第一阶段我们将确定铅候选者，并表现出强烈的，显着的肝肿瘤增强 人源化的OATP敲入小鼠。在第二阶段，我们将对放松性进行铅优化， 药代动力学，安全性和肝图像对比，并选择开发候选者（DC）进行最终临床 翻译。我们将验证我们的DC在肝癌的大鼠和兔模型中，并评估其在大鼠中的安全性。我们 将开发可扩展的，具有成本效益的DC，以将技术转移到CGMP制造商。