HEART IMAGING AGENTS--STRUCTURAL MECHANISTICS STUDY

在过去的18年里，这个项目的主要目标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，我们实验室成功开发了几种交感神经标记物，包括放射性碘化间碘苄基胍（MIBG）、(11C) -间羟麻黄（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）迅速吸收到心脏交感神经中，随后由囊泡单胺转运体（VMAT）储存在囊泡中。然而，虽然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存在问题。本提案的主要目标是生产一种新的交感神经示踪剂，它比我们以前开发的任何示踪剂都更适合于示踪剂动力学分析。这种示踪剂在监测正在寻求停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行性过程的治疗的患者时非常有用。在寻找一种更适合于动力学分析的新的交感示踪剂时，将研究两种不同的方法。(1)通过选择性结构改变降低神经元对NET和VMAT的亲和力，减缓神经元对HED、EPI和PHEN的摄取速率。减慢这些药物的神经元摄取速率可能是进行更严格的动力学分析所必需的。(2)利用一类新的神经元标记物以一种新的方式测量神经网络密度：随后在神经元内不可逆地捕获的神经网络运输底物。我们以[11C]标记的“自杀”MAO抑制剂tranycyproamine和phenelzine的类似物为目标，它们也是NET底物，作为研究这种测量神经元密度的新策略的起点。我们的目标是扩展我们对高亲和力NET抑制剂地西帕明（DMI）极性衍生物作为神经元NET密度标记物的工作，通过[18f]标记我们最有希望的DMI类似物，以更好地研究它们的心肌动力学更长时间。最后，将合成精神兴奋剂甲基卡西酮的[11C]-和[18F]-标记的极性衍生物作为潜在的NET标记物，并确定其体外NET亲和力作为克隆的人类NET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.