HEART IMAGING AGENTS--STRUCTURAL MECHANISTICS STUDY

在过去的18年里，该项目的主要目标是开发可用于临床测量活体心脏交感神经状态的放射性示踪剂。为此，我们实验室成功地使用了几种交感神经标记物，包括放射性碘化Meta碘苄胍（MIBG）、（11 C）-间羟基麻黄碱（HED）、[11 C]肾上腺素（EPI）和[11 C]苯肾上腺素（PHEN）。所有这些药物都被神经元去甲肾上腺素转运蛋白（NET）贪婪地摄取到心脏交感神经中，随后被囊泡单胺转运蛋白（VMAT）储存在囊泡中。然而，虽然这些试剂的非常快速的摄取提供了高质量的心脏图像，但它也使示踪剂动力学建模成为问题。这个建议的一个主要目标是产生一种新的交感神经示踪剂，比我们以前开发的任何示踪剂动力学分析更适合。这种示踪剂在监测接受治疗的患者中将是非常有用的，所述治疗试图停止或逆转在诸如糖尿病自主神经病变和心力衰竭的疾病中看到的神经变性过程。两种不同的方法将在寻找一种新的交感神经示踪剂更适合于动力学分析进行调查。(1)减慢HED、EPI和PHEN的神经元摄取速率，已知选择性结构改变降低它们对NET和VMAT的亲和力。减慢这些药物的神经元摄取速率可能是允许更严格的动力学分析所必需的。(2)用一种新的神经元标记物以新的方式测量NET密度：NET转运底物，其随后被不可逆地捕获在神经元内。我们有针对性的[11 C]-标记的类似物的“自杀”的单胺氧化酶抑制剂反苯环丙胺和苯乙肼，这也是NET基板，作为一个起点，调查这种新的策略，用于测量神经元密度。我们的目标是通过[18 F-标记我们最有前途的去甲丙咪嗪类似物，以更好地研究其心肌动力学，以更长的时间，将我们的工作扩展到高亲和力NET抑制剂地昔帕明（地昔帕明）的极性衍生物作为神经元NET密度的标志物。最后，[11 C]-和[18 F]-标记的极性衍生物的精神兴奋剂甲卡西酮将被合成为潜在的NET标记物和它们的体外NET亲和力确定为克隆的人NET转运蛋白。

The primary goal of this project over the last 18 years has been to develop radiotracers that can be used clinically to measure cardiac sympathetic nerve status in the living human. To this end, our laboratory several successful sympathetic nerve markers, including radio-iodinated meta- iodobenzylguanidine (MIBG), (11C]-meta-hydroxyephedrine (HED), [11C]epinephrine (EPI), and [11C]phenylephrine (PHEN). All of these agents are avidly taken up into cardiac sympathetic nerves by the neuronal norepinephrine transporter (NET) and subsequently stored in vesicles by the vesicular monoamine transporter (VMAT). However, while the very rapid uptake of these agents provides high quality images of heart, it also makes tracer kinetic modeling problematic. A major goal of this proposal is to produce a new sympathetic nerve tracer that is more suitable for tracer kinetic analyses than any we have previously developed. Such a tracer would be extremely useful in monitoring patients undergoing therapies which seek to halt or reverse the neurodegenerative processes seen in diseases such as diabetic autonomic neuropathy and heart failure. Two distinct approaches will be investigated in the search for a new sympathetic tracer more suited to kinetic analysis. (1) slowing the neuronal uptake rate of HED, EPI, and PHEN with selective structural alterations known to reduce their affinity for NET and VMAT. Slowing the neuronal uptake rate of these agents may be all that is necessary to permit more rigorous kinetic analyses. (2) measuring NET density in a new way with a novel class of neuronal markers: NET transport substrates that are subsequently irreversibly trapped within the neuron. We have targeted [11C]-labeled analogs of the 'suicide' MAO inhibitors tranycypromine and phenelzine, which are also NET substrates, as a starting point to investigate this new strategy for measuring neuronal density. We aim to extend our work on polar derivatives of the high affinity NET inhibitor desipramine (DMI) as markers of neuronal NET density by [18F-labeling our most promising DMI analogs to better study their myocardial kinetics out to longer times. Finally, [11C]- and [18F]-labeled polar derivatives of the psychostimulant methcathinone will be synthesized as potential NET markers and their in vitro NET affinities determined as the cloned human NET transporter.