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

描述(申请人提供)：这个项目的目标是开发一种18F标记的放射性药物，用于PET(正电子发射断层扫描)心肌灌注成像。心肌灌注成像(MPI)是成人最常用的核医学程序；美国近60%的核医学研究是为了评估心肌灌注，每年有近1000万项研究。MPI受欢迎的一个原因是它对未来心脏事件的极高预测价值。目前，MPI的研究通常使用单光子放射性药物99mTC-MIBI和99mTC-Tetrofosmin。然而，与单光子成像相比，PET成像为MPI提供了显著的优势，包括更高的空间分辨率；改进的衰减校正，这一点在美国肥胖率上升的情况下非常重要；以及直接测量示踪剂摄取的能力，这在评估全球缺血方面非常重要。另一个动机是目前世界范围内99mTc的短缺。目前使用的PET MPI示踪剂包括82Rb(t1/2=76 S)、[13N]NH3(t1/2=10分钟)和[150]H2O(t1/2=2分钟)。然而，这些试剂受到重大限制，包括82Rb的高成本以及[13N]NH3和[15O]H2O的有限可获得性，这些都需要现场回旋加速器来生产。氟-18具有近乎理想的MPI物理性能(t1/2=110min，2+产率97%，2+能量低)，成本低于82Rb，比[13N]NH3和[15O]H2O有更高的利用率。然而，目前还没有商业上可用的18F标记的MPI放射性药物。众所周知，罗丹明染料会在心脏中积累，因此为18F标记的MPI放射性药物的开发提供了一个有希望的起点。因此，这项提议的核心假设是：基于18F标记的罗丹明染料，可以开发一种用于评估心肌灌注的PET放射性药物。这一基本前提最近在我们的实验室得到了验证，我们观察到18F标记的罗丹明B的酯衍生物在心脏中有很高的蓄积，在肝脏中的蓄积很少(这可能会干扰左心室尖端的显示)，并且血液清除迅速。该项目的具体目标将在这一初步观察的基础上进行扩展，并验证这一假设。为此，我们将(1)开发一种合成方法，以产生高产率、高化学和放射化学纯度以及高比活度的18F标记罗丹明；(2)评估18F标记罗丹明对MPI的重要生物学性质；以及(3)确定哪种罗丹明染料最适合用作MPI放射性药物。这些特定目标的成功实现将导致开发一种用于PET心肌灌注成像的新型有效放射性药物，这将显著改善心脏病患者的临床管理。

DESCRIPTION (provided by applicant): The objective of this project is the development of an 18F-labeled radiopharmaceutical for PET (positron- emission tomography) imaging myocardial perfusion. Myocardial perfusion imaging (MPI) is the most commonly performed nuclear medicine procedure performed in adults; nearly 60% of all nuclear medicine studies in the U.S. are for the evaluation myocardial perfusion, nearly 10,000,000 studies each year. One reason for the popularity of MPI is its extremely high predictive value for future cardiac events. At the present time, MPI studies are usually carried out using the single-photon radiopharmaceuticals 99mTc-MIBI and 99mTc- tetrofosmin. However, PET imaging offers significant advantages over single-photon imaging for MPI including higher spatial resolution; improved attenuation correction, which is of importance because of the increasing rate of obesity in the US; and the ability to directly measure tracer uptake, which is important in the evaluation of global ischemia. An additional motivation is the current worldwide shortage of 99mTc. The PET MPI tracers currently in use include 82Rb (T1/2=76 s), [13N]NH3 (T1/2=10 min), and [15O]H2O (T1/2=2 min). However, these agents suffer from significant limitations including the high cost of 82Rb and the limited availability of [13N]NH3 and [15O]H2O, which require on-site cyclotrons for production. Fluorine-18 has nearly ideal physical properties for MPI (T1/2=110 min, 97% 2+ yield, low 2+ energy), lower cost than 82Rb, and greater availability than [13N]NH3 and [15O]H2O. There are, however, currently no commercially available 18F-labeled MPI radiopharmaceuticals. Rhodamine dyes are known to accumulate in the heart and therefore offer a promising starting point for the development of an 18F-labeled MPI radiopharmaceutical. The core hypothesis of this proposal is, therefore, that: A PET radiopharmaceutical for the evaluation of myocardial perfusion can be developed based on an 18F- labeled rhodamine dye. This basic premise was recently validated in our laboratory when we observed that 18F-labeled ester derivatives of rhodamine B showed very high accumulation in the heart, minimal accumulation in the liver (which can interfere with visualization of the apex of the left ventricle), and rapid blood clearance. The Specific Aims of the project will expand upon this initial observation and validate this hypothesis. To this end, we will (1) develop a synthesis that produces 18F-labeled rhodamines in high yield, high chemical and radiochemical purity, and high specific activity, (2) evaluate the biological properties of 18F- labeled rhodamines that are important for MPI, and (3) determine which rhodamine dye is optimal for use as an MPI radiopharmaceutical. The successful accomplishment of these Specific Aims will result in the development of a novel and effective radiopharmaceutical for myocardial perfusion imaging with PET that will significantly improve clinical management of patients with cardiac disease.