Heart Imaging Agents: A Structural-Mechanistic Study

描述（由申请人提供）：该项目的主要目标是开发用于无创评估心脏交感神经支配的放射性示踪剂。为此，我们的实验室已经成功开发了几种用于心脏交感神经元成像的放射性示踪剂，包括放射性碘化间碘苄基胍（MIBG）， 11C]间羟麻油（HED）和[11C]肾上腺素（EPI）。所有这些示踪剂都被神经元去甲肾上腺素转运蛋白（NET）迅速吸收到心脏交感神经中，并被囊泡单胺转运蛋白（VMAT2）储存在囊泡中。然而，虽然这些药物的快速神经元摄取提供了高质量的图像，但它也使示踪剂动力学分析存在问题。本提案的主要目标是开发具有最佳动力学特性的动力学优越，更多信息丰富的示踪剂，用于定量分析。这种示踪剂将提供比目前可能的更敏感和准确的神经密度测量。这将有助于在糖尿病自主神经病变和心力衰竭等疾病患者的神经丧失变得严重之前检测出早期的去神经支配。早期发现神经丧失对于提供有效的治疗来停止或逆转心脏去神经支配可能是至关重要的。我们假设，放射性标记的NET底物必须具有2个动力学特性，才能成为“理想的”示踪剂动力学分析：(1)缓慢的神经元摄取速率；(2)通过快速有效的囊泡储存，神经元保留时间很长。我们进一步假设具有这些特性的示踪剂可以在已知的对交感神经元发挥有效药理作用的许多胍中找到。一种将碳-11掺入胍类化合物的放射性合成方法将用于合成和评价2个系列的[11C]胍类化合物作为交感神经示踪剂，具有改进的动力学。用N-[11C]鸟腈基团代替N-[11C]甲基进行放射性标记有几个优点，包括更高的极性、抗代谢和在血液中的稳定性。系列一由[11C]苯乙基胍组成。初步研究表明，几种[11C]苯乙基胍具有所需的慢神经元摄取率和长神经元保留时间。为了开发具有理想动力学的[18F]胍，系列II由环氟化苯乙基胍组成。这些将在18f标记最佳制剂之前用hc标记进行评估。[11C]胍类药物的生物评价将从离体大鼠心脏的动力学研究和NET和VMAT2转运动力学的细胞研究开始。有希望的化合物的生物分布将在大鼠中进行测量。最后，用最好的示踪剂对猴子进行微pet成像。这项对[11C]胍类药物的系统研究将导致开发一种具有最佳动力学的示踪剂，用于PET量化心脏交感神经密度。

DESCRIPTION (provided by applicant): The primary goal of this project has been to develop radiotracers for the noninvasive assessment of cardiac sympathetic innervation. To this end, our laboratory has developed several successful radiotracers for imaging cardiac sympathetic neurons, including radioiodinated meta iodobenzylguanidine (MIBG), 11C]meta-hydroxyephedrine (HED) and [11C]epinephrine (EPI). All of these tracers are avidly taken up into cardiac sympathetic nerves by the neuronal norepinephrine transporter (NET) and stored in vesicles by the vesicular monoamine transporter (VMAT2). However, while the very rapid neuronal uptake of these agents provides high quality images, it also makes tracer kinetic analyses problematic. The major goal of this proposal is to develop kinetically superior, more information-rich tracers that possess optimal kinetic properties for quantitative analyses. Such tracers would provide more sensitive and accurate measures of nerve density than are currently possible. This would allow detection of early denervation in patients with diseases such as diabetic autonomic neuropathy and heart failure, before nerve losses become severe. Early detection of nerve losses may be critically important in providing effective therapies to halt or reverse cardiac denervation. We hypothesize that a radiolabeled NET substrate must possess 2 kinetic properties to be 'ideal' for tracer kinetic analyses: (1) a slow neuronal uptake rate, and (2) a very long neuronal retention time, through rapid and efficient vesicular storage. We further hypothesize that a tracer with these properties can be found among the many guanidines known to exert potent pharmacological effects on sympathetic neurons. A radiosynthetic method for incorporating carbon-11 into guanidines will be used to synthesize and evaluate 2 series of [11C]guanidines as sympathetic nerve tracers with improved kinetics. Radiolabeling with a N-[11C]guanyl moiety instead of a N-[11C]methyl group offers several advantages, including higher polarity, resistance to metabolism, and stability in blood. Series I is comprised of [11C]phenethylguanidines. Pilot studies show that several [11C]phenethylguanidines possess the desired slow neuronal uptake rate and long neuronal retention time. In an effort to develop an [18F] guanidine with ideal kinetics, Series II consists of ring-fluorinated phenethylguanidines. These will be evaluated with HC-labeling before 18F-labeling the best agents. Bioevaluation of [11C]guanidines will start with kinetic studies in the isolated rat heart and cellular studies of NET and VMAT2 transport kinetics. The biodistribution of promising compounds will be measured in rats. Finally, microPET imaging in monkeys will be performed with the best tracers. This systematic study of [11C]guanidines should result in the development of a tracer with optimal kinetics for quantifying cardiac sympathetic nerve density with PET.