DAT Binding by Pet in Adult ADHD

描述（由申请人提供）：这是R01申请的第二次重新提交。我们最近使用单光子发射计算机断层扫描（SPECT）和高选择性放射性药物阿托pane，测量了成人ADHD患者的多巴胺转运体（DAT）结合ADHD成人的DAT结合率高出70%。Krause等人部分重复了我们的发现（增加了17%），但van Dyck等人没有重复（没有增加），两者都使用了特异性较低的放射性配体。正电子发射断层扫描（PET）与11C- altropane是理想的测量数据。它比SPECT在更短的采集时间内产生更高的分辨率，改进的信噪比和更少的伪影，并允许动力学建模和估计亲和力和密度。迄今为止，6名成年人和6名对照者在MGH使用[11C]阿曲烷和PET成像，显示DAT结合增加34%。此外，库克和其他人已经证明了多动症与多巴胺转运体缺失的480 bp等位基因之间的联系。为此，本分子成像建议的主要目标是通过专家诊断方法，更大的N(66)，技术上优越的配体（11C- altropane）和最先进的成像（PET），牢固地确定成人ADHD中增加的DAT结合的程度。此外，我们试图扩展先前的发现，以检查密度（B'max）和亲和力（Kd）。这项工作将使ADHD研究领域进入一个分子遗传学和影像学研究相结合的新方向。我们的具体目标如下：目的：采用PET扫描，以11C丙戊烷为检测手段，检测成人ADHD患者的DAT受体结合情况。我们假设，与没有多动症的成年人相比，患有多动症的成年人将有更大的数据绑定，这与精神合并症、性别或年龄无关。此外，我们将分别检查DAT位点的密度和亲和力。2. 目的：探讨DAT与ADHD临床特征的关系。我们假设DAT结合将与a) ADHD症状的严重程度呈正相关；b)神经心理和人际功能障碍。3. 来检查DAT绑定和。a)我们假设DAT结合将与多巴胺转运基因3'-非翻译区40-bp VNTR的480等位基因相关。

DESCRIPTION (provided by applicant): This is the second resubmission of an R01 application. We recently measured dopamine transporter (DAT) binding in adults with ADHD, using single photon emission computed tomography (SPECT) with the highly selective radiopharmaceutical, altropane.[9] DAT binding in was 70% greater Jn adults with ADHD. Our findings were partially replicated by Krause et al., (17% increase) but not replicated by van Dyck et al. (no increase), both using less specific radioligands. Positron emission tomography (PET) with 11C- altropane is ideal to measure DAT. It produces higher resolution, improved signal-to-noise ratio and less artifact than SPECT over a shorter acquisition time and permits kinetic modeling and estimates of affinity and density. To date, 6 adults and 6 controls have been imaged at MGH using [11C]altropane and PET which revealed a 34% increase in DAT binding. Moreover, Cook and others have demonstrated an association between ADHD and the 480-bp allele of the dopamine transporter gone. To this end, the primary goal of this molecular imaging proposal is to firmly establish the magnitude of increased DAT binding in adult ADHD with expert diagnostic methodology, a much larger N (66), a technically superior ligand (11C- altropane) and state-of-the-art imaging (PET). In addition, we seek to extend the previous findings to examine density (B'max) and affinity (Kd). The proposed work should move the field of ADHD research into a new direction in which molecular genetic and imaging studies are combined. Our specific aims are the following: 1. To examine DAT receptor bindinq in adults with ADHD usinq PET scanninq with 11C altropane as the li.qand. We hypothesize that compared to adults without ADHD, adults with ADHD will have greater DAT binding that will not be accounted for by psychiatric comorbidity, gender or age. Furthermore, we will separately examine density of DAT sites and affinity. 2. To examine the relationship of DAT binding to clinical features of ADHD. We hypothesize that DAT binding will be positively correlated with a) severity of ADHD symptoms; and b) neuropsychological and interpersonal dysfunction. 3. To examine the relationship between DAT bindinq and .qenetic risk factors, a) We hypothesize that DAT binding will be associated with the 480 allele of the 40-bp VNTR in the 3'-untranslated region of the dopamine transporter gene.