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

描述（由申请人提供）：本项目的目的是开发用于PET（正电子发射断层扫描）心肌灌注成像的18F标记放射性药物。心肌灌注成像（MPI）是成人中最常进行的核医学程序;在美国，近60%的核医学研究用于评价心肌灌注，每年近10，000，000项研究。MPI流行的一个原因是它对未来心脏事件的极高预测价值。目前，MPI研究通常使用单光子放射性药物99 mTc-MIBI和99 mTc-tetrofosmin进行。然而，PET成像相对于MPI的单光子成像具有显著的优势，包括更高的空间分辨率;改善的衰减校正，这一点非常重要，因为美国肥胖率不断增加;以及直接测量示踪剂摄取的能力，这在评估全脑缺血中非常重要。另一个动机是目前全球99 mTc短缺。 目前使用的PET MPI示踪剂包括82 Rb（T1/2=76 s）、[13 N]NH3（T1/2=10 min）和[15 O]H2O（T1/2=2 min）。然而，这些试剂受到显著的限制，包括82 Rb的高成本和[13 N]NH3和[15 O]H2O的有限可用性，其需要现场回旋加速器用于生产。氟-18对MPI具有接近理想的物理性质（T1/2=110 min，97%2+产率，低2+能量），比82 Rb更低的成本，并且比[13 N]NH3和[15 O]H2O更高的可用性。然而，目前没有市售的18F标记的MPI放射性药物。 已知罗丹明染料在心脏中积累，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，该提议的核心假设是：可以基于18F标记的罗丹明染料开发用于评价心肌灌注的PET放射性药物。这一基本前提最近在我们的实验室中得到了验证，我们观察到18 F标记的罗丹明B酯衍生物在心脏中的蓄积非常高，在肝脏中的蓄积最小（可能干扰左心室心尖的可视化），并且血液清除迅速。该项目的具体目标将扩大这一初步观察，并验证这一假设。为此，我们将（1）开发一种合成方法，以高产率、高化学和放射化学纯度以及高比活度生产18F标记的罗丹明，（2）评价18F标记的罗丹明的生物学特性，这些特性对MPI很重要，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.