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

描述（由申请人提供）：该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）成像心肌灌注。心肌灌注成像（MPI）是成人最常用的核医学程序；美国近60%的核医学研究用于心肌灌注评估，每年近1000万项研究。MPI受欢迎的一个原因是它对未来心脏事件具有极高的预测价值。目前，MPI研究通常使用单光子放射性药物99mTc- mibi和99mTc- tetrofosmin进行。然而，与单光子成像相比，PET成像具有明显的优势，包括更高的空间分辨率；改进了衰减校正，这一点很重要，因为美国的肥胖率正在上升；以及直接测量示踪剂摄取的能力，这对评估全身缺血很重要。另一个动机是目前全球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 min）和[15O]H2O （T1/2=2 min）。然而，这些试剂受到很大的限制，包括82Rb的高成本和[13N]NH3和[15O]H2O的有限可用性，这需要现场回旋加速器进行生产。氟-18具有近乎理想的物理性质（T1/2=110 min， 97% 2+产率，低2+能量），比82Rb成本低，比[13N]NH3和[15O]H2O的可用性更高。然而，目前市面上还没有18f标记的MPI放射性药物。已知罗丹明染料会在心脏中积聚，因此为开发18f标记的MPI放射性药物提供了一个有希望的起点。因此，本提案的核心假设是：可以基于18F标记的罗丹明染料开发用于心肌灌注评估的PET放射性药物。这个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的积累非常高，在肝脏中的积累很少（这会干扰左心室顶点的可视化），并且血液清除迅速。该项目的具体目标将扩展这一初步观察并验证这一假设。为此，我们将(1)开发一种合成方法，生产高产量、高化学和放射化学纯度、高比活性的18F标记罗丹明，(2)评估18F标记罗丹明对MPI的重要生物学特性，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一种新型有效的PET心肌灌注成像放射性药物的开发，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.