Acute-infarct selective cardiac MRI contrast agent

描述(申请人提供)：对急性和慢性心肌梗死进行可靠的诊断鉴别将对心脏外科医生和介入心脏科医生大有裨益。这种区分可以用来决定哪些血管以及以什么顺序重新开放或绕过。MRI是一种本质上无创的诊断工具，延迟增强MRI技术能够通过造影剂(如MagnevistZ)的积聚来突出梗死灶，导致梗死区心肌组织的MRI强度高强化。然而，不幸的是，利用目前可用的造影剂，这项技术不能区分急性(即相对新鲜的)脑梗塞和慢性(即陈旧性脑梗塞)。最近提出的一项新技术，使用在注射造影剂之前拍摄的T2加权图像，有时确实可以区分急性和慢性脑梗塞，但由于各种因素，它不能以可预测的方式做到这一点。这种不可预测性从根本上阻止了这项技术在临床决策中的使用。根据我们的初步数据，我们提出使用一种新的心肌造影剂，Gd-ABE-DTTA，它通过引起信号高强化来选择性地突出急性脑梗塞，但不会导致超过2周的脑梗塞的高强化。使用这种试剂的核磁共振成像将以一种高度可靠的方式对急性和慢性脑梗塞进行理想的区分。我们的长期目标是，使用犬的心肌梗死模型，证明实践“血管分流”的实用能力，表征其应用的参数，并探讨分化的组织机制。在这些参数中，将确定最佳剂量、梗死后信号高强化出现的最早时间以及作用的时间窗口(最早和最晚时间)。作为第一步，在这个第一阶段项目中，将实现一个有限的目标，以充分的统计学意义证明该试剂显示早期急性(小于2天)和晚期急性(大于8天)梗死之间的区别的能力。一旦达到这一有限的目标，将提交第二阶段申请。在实现上述长期目标的第二阶段之后，将采取步骤实现商业化。

DESCRIPTION (provided by applicant): Reliable diagnostic differentiation between acute and chronic myocardial infarcts would be of great benefit for cardiac surgeons and interventional cardiologists. Such differentiation could be used to make decisions about which vessels and in what order would be reopened or bypassed. MRI is an intrinsically noninvasive diagnostic tool and the Delayed Enhancement MRI technique is capable of highlighting infarct by the accumulation of contrast agents (e.g., MagnevistZ) into it, causing MRI intensity hyperenhancement in infarcted myocardial tissue. Unfortunately, however, the technique, with the presently available contrast agents, does not differentiate between acute, i.e., relatively fresh, infarcts and chronic, i.e., old infarcts. A recently proffered addition to this technique, the use of T2-weighted images taken before the administration of the contrast agent, does sometimes distinguish acute infarcts from chronic infarcts but due to various factors it does not do so in a predictable manner. This unpredictability essentially prevents the use of this technique in clinical decision making. Based on our preliminary data, we offer the use of a new myocardial contrast agent, Gadolinium-ABE-DTTA, which selectively highlights acute infarcts by causing signal hyperenhancement, yet does not cause hyperenhancement in infarcts that are beyond 2 weeks old. MRI imaging, using this agent, would allow the sought-after differentiation of acute from chronic infarct in a highly reliable manner. Our long term objective, using a canine model of myocardial infarction, is to prove the practical ability to exercise "vessel triage", to characterize the parameters for its application, and to investigate the tissue mechanism of the differentiation. Among the parameters the optimal dose, the earliest post-infarct time of the emergence of signal hyperenhancement, and the time window (earliest and latest time) of the effect will be determined. As a first step, in this Phase I project a limited objective will be achieved, to prove with sufficient statistical significance the ability of this agent to show differentiation between early acute (less than 2 days old) and late acute (more than 8 days old) infarcts. A Phase II application will be submitted once this limited objective is met. Following Phase II, which will pursue the long term objective described above, steps will be taken towards commercialization.