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

项目摘要 在美国，心血管疾病每年造成60多万人死亡，其中一半以上是由心血管疾病引起的。 这些都是由于冠心病（CHD）。心肌灌注成像（MPI）是目前最重要的 评估CHD的有效工具，根据最新估计，这项技术占 >50%的成人核医学研究，2014年近600万次扫描。目前，大多数研究 使用99 mTc-MIBI和99 mTc-tetrofosmin进行，尽管SPECT（单次SPECT）有显著的局限性， 光子发射计算机断层扫描），包括比PET（正电子发射断层扫描）更低的空间分辨率 断层扫描）;缺乏常规衰减校正，这在越来越多的国家中特别重要。 肥胖人群;以及测量心肌血流量（MBF）的挑战，这对准确测量 评估全脑缺血和微血管疾病。这项研究，“一种新的F-18 PET心肌 基于罗丹明染料的灌注放射性药物”建立在目前资助的 同一标题，1 R 01 HL 108107 -01，于2017年1月31日结束。与基础R 01一样， 本项目的目的是开发一种用于PET成像的18F标记放射性药物， 心肌灌注最初项目的具体目标已经基本实现;因此，虽然我们的 中心假设保持不变，即，PET心肌灌注显像剂可以被开发出来， 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，以启动首次 在下一个项目期间进行人类研究。我们已经证明，18F标记的罗丹明染料积累， 令人印象深刻的心脏，这证实了他们的显着潜力，PET MPI放射性药物。的 因此，该提案的中心假设没有改变： 可以基于18F标记的罗丹明染料来进行心肌灌注的评价。我们有 在我们的实验室中测试并验证了这一基本前提，发现18F标记的二甘醇酯 罗丹明6 G的衍生物（[18 F] Rho 6 G）在心脏中显示出非常高的蓄积， 肝脏和快速血液清除。虽然18 F-Rho 6 G作为MPI代理已经显示出很大的希望，但我们没有 还不知道它是否能在人体中发挥最佳作用。因此，我们将探索其他罗丹明样化合物， 用于MPI的潜在PET放射性示踪剂。因此，新的具体目标将首先建立在我们对18F的研究结果的基础上， 通过a）用[18 F] Rho 6 G进行首次人体研究; B）测量18 F-Rho 6 G的提取分数， Rho 6 G，用于临床上有用的MPI放射性药物的关键参数;以及c）评估多个 新的罗丹明衍生物，并评估替代核心，预计可能需要一个 用于人类的罗丹明染料的替代品。这些具体目标的成功实现将导致 开发一种新的和有效的PET放射性药物的MPI，将显着改善 通过提供准确的心肌灌注测量，对CHD患者进行临床管理。

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.