HEART IMAGING AGENTS--STRUCTURAL MECHANISTICS STUDY

在过去的18年里，该项目的主要目标一直是开发可用于临床测量活人心脏交感神经状态的放射性示踪剂。为此，本实验室研制了几种成功的交感神经标记物，包括放射性碘标记的间碘间苯基胍(MIBG)、(11C)-间羟基麻黄碱(Hed)、[11C]肾上腺素(EPI)和[11C]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体(Net)贪婪地吸收到心脏交感神经中，然后由囊泡单胺转运体(VMAT)储存在小泡中。然而，尽管这些试剂的快速吸收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。这项提议的一个主要目标是生产一种新的交感神经示踪剂，它比我们之前开发的任何一种示踪剂都更适合示踪剂动力学分析。这种示踪剂在监测接受治疗的患者时将非常有用，这些治疗试图阻止或逆转糖尿病自主神经病变和心力衰竭等疾病中出现的神经退化过程。将研究两种不同的方法，以寻找更适合动力学分析的新的交感示踪剂。(1)通过选择性的结构改变降低Hed、EPI和phen对Net和VMAT的亲和力，减缓神经元对Hed、EPI和phen的摄取速度。减缓这些药物的神经元摄取速度可能是允许进行更严格的动力学分析所必需的。(2)用一类新的神经元标记物以一种新的方式测量净密度：随后不可逆地困在神经元内的净运输底物。我们已经瞄准了[11C]标记的‘自杀’MAO抑制剂三环丙胺和苯乙肼的类似物，它们也是净底物，作为研究这一测量神经元密度的新策略的起点。我们的目标是通过[18F-标记我们最有希望的DMI类似物来扩展我们的工作，将高亲和力网络抑制剂地塞帕明(DMI)的极性衍生物作为神经元网络密度的标记物，以更好地研究它们的心肌动力学。最后，[11C]和[18F]标记的精神刺激剂美卡西酮的极性衍生物将被合成作为潜在的网络标记，并将它们的体外网络亲和力确定为克隆的人网络转运体。

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.