A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes

项目摘要 美国每年有60多万人死于心血管疾病，其中一半以上死于心血管疾病 其中一些是由于冠心病(CHD)。心肌灌注成像(Mpi)是目前最重要的 评估冠心病的有效工具，根据最新的估计，这项技术解释了 2014年，在所有针对成人的核医学研究中，有50%的患者接受了近600万次扫描。目前，这些研究大多 使用99mTC-MIBI和99mTC-Tetrofosmin进行检查，尽管SPECT(单一的 用于空间分辨率低于正电子发射的MPI的光子发射计算机层析成像 断层扫描)；缺乏常规衰减校正，这在日益增长的 肥胖人群；以及测量心肌血流量(MBF)的挑战，这对准确地 评估全球缺血和微血管疾病。本研究是一种新型F-18PET心肌 以罗丹明染料为基础的灌注放射性药物“建立在目前获得资助的 相同标题，1 R01 HL108107-01,2017年1月31日结束。与基础性R01中一样，主要 本项目的目标是开发一种18F标记的放射性药物，用于PET成像 心肌灌注。原来项目的具体目标已基本实现；因此，虽然我们的 中心假设保持不变，即可以开发出一种PET心肌灌注显像剂 基于18F标记的罗丹明染料，我们已经收集了足够的初步结果来启动第一个在... 人类--在下一个项目阶段进行研究。我们已经证明了18F标记的罗丹明染料会积累 在心脏方面令人印象深刻，这证实了它们作为PET MPI放射性药物的巨大潜力。这个 因此，这一提议的中心假设是不变的：一种用于 可以基于18F标记的罗丹明染料来评估心肌灌注。我们有 在实验室对这一基本前提进行了测试和验证，发现18F标记的二乙二醇酯 罗丹明6G的衍生物([18F]Rho6G)在心脏中有很高的蓄积，在心脏中的蓄积最低 肝脏，和快速的血液清除。虽然18F-Rho6G作为MPI代理商表现出了巨大的希望，但我们并没有 但知道它是否会在人类身上表现得最好。因此，我们将探索其他罗丹明类化合物，如 潜在的用于MPI的PET放射性示踪剂。因此，新的具体目标将首先建立在我们与18F- 通过a)与[18F]Rho6G进行第一次人体研究；b)测量18F- Rho6G，临床上有用的MPI放射性药物的关键参数；以及c)评估一些 新的罗丹明衍生物，并评估替代核心，以预测可能需要 人类使用的罗丹明染料的替代品。我们成功地实现这些具体目标将导致 开发一种新的、有效的治疗MPI的PET放射性药物，将显著改善 通过提供准确的心肌灌注测量对冠心病患者的临床管理。

Project Summary Cardiovascular disease is responsible for more than 600,000 deaths each year in the US, and more than half of these are due to coronary heart disease (CHD). Myocardial perfusion imaging (MPI) is one of the most effective tools for assessing CHD, and according to the most recent estimate, this technique accounts for >50% of all nuclear medicine studies in adults, nearly 6 million scans in 2014. At present, most of these studies are carried out using 99mTc-MIBI and 99mTc-tetrofosmin, despite the significant limitations of SPECT (single photon emission computed tomography) for MPI including lower spatial resolution than PET (positron-emission tomography); the lack of routine attenuation corrections, which are of particular importance in an increasingly obese population; and the challenge of measuring myocardial blood flow (MBF), which is critical to accurately evaluating global ischemia and microvessel disease. This investigation, “A Novel F-18 PET Myocardial Perfusion Radiopharmaceutical based on Rhodamine Dyes,” builds upon a currently funded project of the same title, 1 R01 HL108107-01, that concludes on 1/31/2017. As in the foundational R01, the primary objective of this project is to develop an 18F-labeled radiopharmaceutical for PET imaging of myocardial perfusion. The Specific Aims of the original project have been largely fulfilled; and thus, while our central hypothesis remains the same, i.e., that a PET myocardial perfusion imaging agent can be developed based on an 18F-labeled rhodamine dye, we have gathered sufficient preliminary results to initiate a first-in- human-study in the next project period. We have demonstrated that 18F-labeled rhodamine dyes accumulate impressively in the heart, which confirms their significant potential as PET MPI radiopharmaceuticals. The central hypothesis of this proposal is, therefore, unchanged: A PET radiopharmaceutical for the evaluation of myocardial perfusion can be developed based on an 18F-labeled rhodamine dye. We have tested and validated this basic premise in our laboratory and found that the 18F-labeled diethyleneglycol ester derivative of rhodamine 6G ([18 F]Rho6G) shows very high accumulation in the heart, minimal accumulation in the liver, and rapid blood clearance. While 18 F-Rho6G has shown great promise as an MPI agent, we do not yet know if it will perform optimally in humans. Thus, we will explore additional rhodamine-like compounds as potential PET radiotracers for MPI. Accordingly, the new Specific Aims will first build upon our findings with 18F- Rho6G by a) carrying out a first-in-human study with [18F]Rho6G; b) measuring the extraction fraction of 18F- Rho6G, a critical parameter for a clinically useful MPI radiopharmaceutical; and c) evaluating a number of novel rhodamine derivatives and also assessing alternatives cores in anticipation of the possible need for an alternative to rhodamine dyes for human use. Our successful accomplishment of these Specific Aims will lead to the development of a novel and effective PET radiopharmaceutical for MPI that will significantly improve clinical management of patients with CHD by providing an accurate measure of myocardial perfusion.