Name: investigations on the ga(iii) complex of eob-dtpa and its 68ga radiolabeled analogue
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Description: Watch this Scientific Journal Video about Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue at JoVE.com

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1. EOB-DTPA和Ga的制备EOB-DTPA] 注意:使用前请先咨询的使用有机溶剂，耐酸，耐碱所有相关的材料安全数据表（MSDS）。执行所有步骤，在通风橱中，并使用个人防护用品（防护眼镜，手套，实验室外套）。 <ol><li> 从gadoxetic酸EOB-DTPA的分离 <ol><li>花费3毫升0.25M的gadoxetic酸注射溶液到烧瓶中。草酸的500毫克（5.6毫摩尔）添加到搅拌的溶液中。 </li><li>搅拌1小时后，通过使用减压玻璃料过滤悬浮液。用3毫升的水洗涤残余物三次，分别。 </li><li>合并的含水滤液和装备有pH电极的溶液。添加12M盐酸向滤液直到pH为约-0.1。 </li><li> 在真空中除去溶剂，得到一种无色残余物。在惰性气体下储存。 </li><li>彻底清洗残余物（至少三个次），用乙酸乙酯以除去过量的草酸。干燥在真空下将残余物。 </li><li>再溶解在2ml水，残余物在室温下，然后冷却在冰浴中的溶液中。不除去冰浴，加入0.5M的氢氧化钠水溶液逐滴直至形成一种无色胶固体观察。 </li><li>通过倾析除去水。固体两次用1毫升冷水冲洗。干燥该固体在真空下 ，得到第一个产物级分。 </li><li>隔离的倾析水通过柱色谱法（二氧化硅，甲醇/水4/1）将合并的级分的第二产品级分。24 在真空中除去溶剂。 </li><li>如果这样得到的固体是不是纯白色，再溶解它在1ml水中，加入10毫升乙醇，随后10毫升二乙醚中以沉淀出产物。通过采用减压真空干燥玻璃料过滤。 </li><li>结合无论EOB-DTPA的固体成分并进行NMR光谱，25质谱26和元素分析27。 </li></ol></li><li> 嘎的合成EOB-DTPA] 注意:在干燥惰性气氛下储存固体镓（III），氯化，因为在与空气，水份或油脂分解接触发生，导致腐蚀性烟雾和形成的黄色，棕色或黑色杂质。 <ol><li>由镓（III），氯化1.94克（11.0毫摩尔）溶解于100ml水制备0.11 1M贮存液。稀释加入1ml 25％氨水溶液用4毫升水。 </li><li>溶解EOB-DTPA的80毫克（0.15毫摩尔）在10毫升水的烧瓶中。如果需要的话，加热溶剂以达到完全溶解。 </li><li>添加镓（III），氯化原液1.4毫升（0.15毫摩尔）。装备有搅拌器和pH电极的烧瓶中。加稀氨水溶液中滴加直至溶液的pH为约4.1。在搅拌滚装嗡温度30分钟。 </li><li> 在真空中除去溶剂。放置在一烧瓶中的残余物中，配有中央和平行的侧颈部stillhead。装备中央颈部用冷却手指和侧颈部用真空泵出口</li><li>加热减压（125℃，0.6毫巴）的残基。周期性地从冷却手指和静止头从烧瓶的上部用微湿布除去升华氯化铵（如玻璃表面的白色涂层可见），以及。继续这个过程，直到有新的升华没有明显的形成。 </li><li>分别取出的氯化铵最后的痕量三次用0.5毫升热甲醇洗涤残余物。干燥真空无色残余物。执行NMR光谱，25质谱26和元素分析27。 </li></ol></li></ol> 2.一般标记过程注意:所有前periments包括与放射性物质直接或间接接触，必须仅通过受过训练的人员进行。请使用适当的屏蔽设备。单独收集任何放射性废物和储存，并按照现行规定处理。 <ol><li> 发电机的洗脱 注:绑定为氧化物的十二烷基3,4,5-三羟基苯二氧化硅母核素一个40毫居里68锗/ 68镓发生器使用。洗脱和纯化可以手动进行，或者，如在此过程中的情况下，作为使用蠕动泵和分配器单元组合的自动化过程。 <ol><li>制备的5.5米的解决方案，1.0M和0.05M的盐酸。制备的5.0微米含有25微升的每毫升5.5摩尔的盐酸氯化钠溶液。通过组合4.1克乙酸钠，加入1ml的HCl（30％）和2.5毫升冰醋酸和水的混合物稀释至50ml制备的pH 4.6的缓冲溶液。 </li><li> PRECondition对PS-H +盒通过用1ml的1.0M的盐酸，随后5ml水慢慢冲洗它。 </li><li>用4ml的0.05M盐酸洗脱发生器的二氧化硅柱12装入68镓洗脱液上对PS-H +墨盒。 </li><li>冲洗盒用5毫升水，随后用5毫升的空气干燥。从盒1毫升5.0微米酸化氯化钠溶液洗脱68镓28 </li></ol></li><li> EOB-DTPA的标签与68嘎 <ol><li>溶解EOB-DTPA的1毫克（1.9微摩尔）在1毫升水中。从该溶液中取100微升（0.19微摩尔）和9.9毫升水稀释它们，以制备19微米（10微克/毫升）的EOB-DTPA的原液。 </li><li>删除50微升（相当于22-29活度）含68嘎溶液，放入瓶中。加EOB-DTPA的19毫米原液的50微升（0.5微克）和300微升ö˚F缓冲到pH升至4.0。简要地摇动并孵育在室温下将溶液5分钟。除去1-5微升的等分试样，并把通过HPLC或TLC分析。 </li><li> 。水/三氟乙酸（99.9％/ 0.1％），B - -乙腈/三氟乙酸（99.9％/ 0.1％），梯度A:在反相（RP）C18柱29使用以下流动相进行无线HPLC分析:06分钟80％A→0％A（0.5毫升/分钟），610分钟0％A（0.5毫升/分钟）。 </li><li>确定的无线型HPLC信号作为曲线下面积的峰强度。计算出示踪剂的标记率如放射化学纯度（RCP）如下: RCP = A 嘎EOB-DTPA /（A 嘎 + A 嘎EOB-DTPA）∙100％ Ga的-EOB-DTPA:在68嘎[EOB-DTPA]的曲线下面积 Ga的:下免费68嘎曲线下面积</li></ol></li></ol> 3.标记效率<ol><li>执行程序的标签作为描述d在部分2，使用一个一致的范围开始68镓洗脱液活性， 例如，22-29活度（40-140微升，取决于洗脱物的新鲜度）。 </li><li>添加所需的缓冲溶液的量以调节pH至3.8-4.0（40-190微升，这取决于68镓洗脱液的体积上）。添加所需的配体原液量（10-70微升19毫溶液）。 </li><li>添加所需量的水到每个标记探针的总体积调整至1.75毫升调匀并让样品静置在室温下5分钟。在第2节，以确定标记率进行HPLC分析。 </li><li>执行与0.1微克步骤0.1微克和0.7之间微克配位体的量的标记过程。一式三份每个配体浓度进行实验。计算平均产量和标准偏差。 </li></ol> 4. 体外稳定性<ol><li> 一般≥10rocedure和准备<ol><li>在200毫升的去离子水溶解的磷酸盐缓冲盐水的片剂（PBS）中以制备PBS原液10mM的磷酸盐浓度。 </li><li>用0.5微升EOB-DTPA原液进行22-29活度68嘎的标签，如第2部分所述根据不同的68嘎洗脱液的体积，调节缓冲量，如在第3节撤柜样本描述含6-12活度示踪剂进行稳定度测量标签解决方案。 </li><li>上用0.1M含水柠檬酸钠作为洗脱液80毫米硅胶被覆铝板进行无线TLC分析，并用薄层色谱放射性扫描器分析板30确定TLC信号的强度为曲线下面积。计算出示踪剂的RCP如下: RCP = A 嘎EOB-DTPA /（A-免费嘎 + A 嘎EOB-DTPA + A 嘎胶体 ）∙100％ Ga的-EOB-DTPA:在68嘎[EOB-DTPA]的曲线下面积 Ga的免费电话 :下免费68嘎曲线下面积 Ga的胶体 :面积在68胶体嘎曲线</li><li>计算RCP 吨 / RCP 0为每个时间点。积从而标准化RCP 与自出发点t = 0分钟的时间差。 RCP T =在时间点t 68嘎[EOB-DTPA]的RCP。 RCP 0 = RCP 68嘎[EOB-DTPA]在t = 0分钟。 </li></ol></li><li> 在磷酸盐缓冲盐水稳定性（A）中 <ol><li>到65微升的标记溶液添加的PBS原液15​​0微升和60微升的氢氧化钠溶液（0.1M）将pH提高到7.4。调匀。 </li><li>除去1-5微升等分进行TLC分析（&#39;起点&#39;）。立即孵化器解决方案存储在37℃，取出等分在代表进行TLC分析经3小时ative时间点。 </li></ol></li><li> 朝过量载脂蛋白 -transferrin的在PBS中的稳定性（B）中 <ol><li>至120微升的标记溶液添加的PBS原液50微升和430微升的氢氧化钠溶液（0.1M）将pH提高到7.4。添加40微升载脂蛋白 -transferrin（25毫克/毫升）的溶液。调匀。 </li><li>除去1-5微升等分进行TLC分析（&#39;起点&#39;）。立即在培养箱的溶液储存于37℃，取出等分试样在代表时间点超过3小时，从而进行TLC分析。 </li></ol></li><li> 人血清中的稳定性（C） <ol><li>到500微升的人血清中添加的标记溶液25微升和45微升的氢氧化钠溶液（0.1M）将pH提高到7.4。调匀。 </li><li>除去1-5微升等分进行TLC分析（&#39;起点&#39;）。立即存储在一个INCU溶液乌兰巴托37℃，取出等分在代表时间点超过3小时进行TLC分析。 </li></ol></li></ol> 5.确定分配系数的LogD <ol><li>如第2中所述为50微升的标记溶液添加的PBS原液20微升和170微升的氢氧化钠溶液（0.1M）将pH升高到7.4进行标记的程序。 </li><li>从解决方案支取200微升，放入一个塑料V-瓶。加入200μl 正辛醇的。关闭小瓶涡旋2分钟。然后在1600 xg离心离心样品5分钟。 </li><li>从n辛醇相和各水相取出的40微升一式三份，并把它们放在单独的V-小瓶。要小心，不要混淆层。 </li><li>测量在30秒的伽马井计数器各样品的活性。对于每个样品立即重复测量两次，并计算其平均活动ᾹŤ </子&gt;以每分钟计数（CPM）。列出从而得到ᾹT，W1，ᾹT，W2和ᾹT，W3（水样中的活动），并ᾹT，O1，ᾹT，O2，ᾹT，O3与各自沿（在正辛醇活动）他们的决心的时间点t。 </li><li>定义的最后一个样本为t 0的测量的时间点。确定并通过计算ΔT= TT 0列出Δt的以分钟。执行Ᾱ 吨衰变校正，使用下面的公式: Ᾱ0 =ᾹT·2（ΔT/ 68分钟）。 </li><li>计算Ᾱ0，W为平均Ᾱ0，W 1，Ᾱ0，W2和Ᾱ0，W3以及Ᾱ0，O作为平均Ᾱ0，O1，Ᾱ0，O2和Ᾱ0，O3。使用下列公式计算logD: logD =日志[（Ᾱ <sub&gt; 0，O·40微克）/（Ᾱ0，W·33微克）。 </li><li>执行一式三份整个实验和计算平均logD与标准偏差一起。 </li></ol>

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The authors have nothing to disclose.

EOB-DTPA是通过多步骤合成33访问，但可能只是以及由含有gadoxetic酸可用的造影剂中分离。为了这个目的，中央的Gd（III）离子可以与过量草酸的沉淀。除去钆（Ⅲ）草酸盐和草酸后的配位体可以通过沉淀在冷水中，在pH 1.5分离。然而，为了增强滤液产量柱色谱可以代替或作为后续程序执行的。任一方法产生的70％的总产率的分析纯的配体（ 图1-3， 表1）。 <p class...

Gadoxetic酸，对配体的钆（III）络合物的EOB-DTPA 1的通用名称，是在肝胆磁共振成像（MRI）。2,3-一个常用的造影剂由于其特异性摄取由肝细胞和高百分比肝胆排泄它使局灶性病变和肝脏肿瘤的本地化。2-5然而，MRI技术有一定的局限性（如造影剂毒性，患者的幽闭恐惧症或金属植入物的应用受到限制）调用的替代诊断工具。 正电子发射断层扫描（PET）是一种分子成像方法，其中，一种放射性物质（示踪）的少量施用，在其它在体内的分布由PET扫描器记录6 PET是一种动态的方法，其允许高图像的空间和时间分辨率以及结果的量化，而无需处理MRI造影剂的副作用。所获得的代谢信息的信息值可与来自其他成像方法接收解剖数据进一步增加组合，最通常通过在PET / CT扫描仪计算机断层扫描（CT）的混合成像实现的。 适用于PET示踪剂的化学结构必须包括用作正电子发射放射性同位素。正电子有一个短暂的寿命，因为它们几乎立即消灭与周围组织的原子炮弹电子。通过湮灭与运动的相反方向的两个511keV的伽玛光子发射，这是由PET扫描器记录。-7,8-为了形成示踪剂，PET的核素可以共价结合到分子，如在2-脱氧的情况下2- [18 F] fluoroglucose葡萄糖（FDG），是最广泛使用的PET示踪剂。7然而，核素也可以形成配位键合到一个或多个配体（ 如[68镓] -DOTATOC 9,10）或溶解无机盐）施加（ 例如，[18 F]氟化物钠11。总而言之，示踪剂的结构是至关重要的，因为它决定了它的生物分布，代谢和排泄行为。 合适的PET核素应该结合像便利正电子的能量和可用性，以及半衰期足够预期调查有利特征。 68镓核素已成为PET的字段的必要的力，在过去的二十年。12,13这主要是由于通过一个发电机系统其可用性，它独立地允许在现场标签从回旋加速器的附近。在一台发电机，母核素68戈被吸收在从该子体核素68镓洗脱，随后标记，以一个合适的螯合剂的一列。6,14由于68镓核素的存在是为繁琐耳鼻喉科阳离子就像钆（III）10,13，螯合EOB-DTPA 68嘎，而不是将产生复杂的具有相同的整体负电荷的gadoxetic酸。相应地，68镓示踪剂可能与适宜用于PET成像合并相似的特性肝特异性。虽然gadoxetic酸购买并施用二钠盐，在下面的上下文中，我们将称其为钆〔EOB-DTPA]和非放射性镓（Ⅲ）配合物作为镓[EOB-DTPA]，或68镓[ EOB-DTPA]为方便起见放射性标记组分的情况下。 要用作PET示踪剂，放射性金属配合物需要被广泛地在体外第一检查，在体内或离体实验评估其适用性。要确定相应的医学难题的适用性，各种示踪特征，如生物分布行为和清除轮廓，稳定性，器官特异性和细胞或Tissu酒店Ë摄取需要进行调查。由于它们的非侵入性的性质， 在体外测定常常之前在体内实验进行。人们普遍承认，DTPA及其衍生物是有限的适用性如由于这些配合螯合剂为68镓缺乏动力学惰性，导致同等快速分解的，当体内施用。14-20这主要是通过充当载脂蛋白转引起竞争对手68嘎血浆。然而，我们研究了关于在肝胆成像，其特征在于，可在数分钟内提供诊断信息后注入3,4,21-23，从而不一定需要长期示踪剂稳定性及其可能的应用这种新的示踪剂。为此目的，我们从gadoxetic酸分离EOB-DTPA和最初与天然镓（Ⅲ），它存在两个稳定同位素，69 Ga和71的混合物进行的络合</SUP&gt;嘎。由此获得的复杂的担任非放射性标准68的Ga以下螯合。我们采用建立的方法，同时评估其是否适合确定EOB-DTPA的68 Galabeling效率，并探讨新的68嘎示踪剂的亲脂性及其在不同介质中的稳定性。

<table><tbody><tr><td>primovist</td><td>Bayer</td><td>-</td><td>0.25 M</td></tr><tr><td>gallium(III) chloride</td><td>Sigma-Aldrich Co.</td><td>450898</td><td></td></tr><tr><td>water (deionized)</td><td>-</td><td>-</td><td>tap water deionizing equipment by Auma-Tec GmbH</td></tr><tr><td>hydrochloric acid 12 M</td><td>VWR</td><td>20252.29</td><td></td></tr><tr><td>sodium hydroxide</td><td>Polskie Odczynniki Chemiczne S.A.</td><td>810925429</td><td></td></tr><tr><td>oxalic acid</td><td>Sigma-Aldrich Co.</td><td>75688</td><td></td></tr><tr><td>ethyl acetate</td><td>Brenntag GmbH</td><td>10010447</td><td></td></tr><tr><td>silica gel</td><td>Merck KGaA</td><td>1.10832.9025</td><td>Geduran Si 60 0.063-0.2&amp;nbsp;mm</td></tr><tr><td>TLC silica gel 60 F254</td><td>Merck KGaA</td><td>1.16834.0001</td><td></td></tr><tr><td>methanol</td><td>VWR</td><td>20903.55</td><td></td></tr><tr><td>ethanol</td><td>Brenntag GmbH</td><td>10018366</td><td></td></tr><tr><td>eiethylether</td><td>VWR</td><td>23807.468</td><td>stored over KOH plates</td></tr><tr><td>ammonia solution (25%)</td><td>VWR</td><td>1133.1</td><td></td></tr><tr><td>pH electrode</td><td>VWR</td><td>662-1657</td><td></td></tr><tr><td>stirring and heating unit</td><td>Heidolph</td><td>505-20000-00</td><td></td></tr><tr><td>pump</td><td>Ilmvac GmbH</td><td>322002</td><td></td></tr><tr><td>frit</td><td>-</td><td>custom design</td><td></td></tr><tr><td>NMR spectrometer</td><td>Bruker Coorporation</td><td>-</td><td>Ultra Shield 400</td></tr><tr><td>mass spectrometer</td><td>Thermo Fisher Scientific Inc.</td><td>-</td><td></td></tr><tr><td>elemental analyser</td><td>Hekatech GmbH Analysentechnik</td><td>-</td><td>EuroVector EA 3000 CHNS</td></tr><tr><td>deuterated water D&lt;sub&gt;2&lt;/sub&gt;O</td><td>euriso-top</td><td>D214</td><td>99.90% D</td></tr><tr><td colspan="4">&lt;strong&gt;Material/Equipment required for labeling procedures&lt;/strong&gt;</td></tr><tr><td>&lt;sup&gt;68&lt;/sup&gt;Ge/&lt;sup&gt;68&lt;/sup&gt;Ga generator</td><td>ITG Isotope Technologies Garching GmbH</td><td>A150</td><td></td></tr><tr><td>pump and dispenser system</td><td>Scintomics GmbH</td><td>-</td><td>Variosystem</td></tr><tr><td>hydrochloric acid 30% (suprapur)</td><td>Merck KGaA</td><td>1.00318.1000</td><td></td></tr><tr><td>water (ultrapur)</td><td>Merck KGaA</td><td>1.01262.1000</td><td></td></tr><tr><td>sodium chloride (suprapur)</td><td>Merck KGaA</td><td>1.06406.0500</td><td></td></tr><tr><td>sodium acetate (suprapur)</td><td>Merck KGaA</td><td>1.06264.0050</td><td></td></tr><tr><td>glacial acetic acid (suprapur)</td><td>Merck KGaA</td><td>1.00066.0250</td><td></td></tr><tr><td>sodium citrate dihydrate</td><td>VEB Laborchemie Apolda</td><td>10782</td><td>&gt;98.5%</td></tr><tr><td>PS-H&lt;sup&gt;+&lt;/sup&gt; Cartridge (S)</td><td>Macherey-Nagel</td><td>731867</td><td>Chromafix</td></tr><tr><td>&lt;em&gt;apo&lt;/em&gt;-Transferrin</td><td>Sigma-Aldrich Co.</td><td>T2036</td><td></td></tr><tr><td>PBS buffer (tablets)</td><td>Sigma-Aldrich Co.</td><td>79382</td><td></td></tr><tr><td>human serum</td><td>Sigma-Aldrich Co.</td><td>H4522</td><td>from human male AB plasma</td></tr><tr><td>flasks, columns, &lt;em&gt;etc.&lt;/em&gt;</td><td></td><td>custom design</td><td></td></tr><tr><td>pH electrode</td><td>Knick Elektronische Messger&amp;auml;te GmbH &amp;amp; Co. KG</td><td>765-Set</td><td></td></tr><tr><td>binary pump (HPLC)</td><td>Hewlett-Packard</td><td>G1312A (HP 1100)</td><td></td></tr><tr><td>UV Vis detector (HPLC)</td><td>Hewlett-Packard</td><td>G1315A (HP 1100)</td><td></td></tr><tr><td>radioactive detector (HPLC)</td><td>EGRC Berthold</td><td></td><td></td></tr><tr><td>HPLC C-18-PFP column</td><td>Advanced Chromatography Technologies Ltd.</td><td>ACE-1110-1503/A100528</td><td></td></tr><tr><td>HPLC glass vials</td><td>GTG Glastechnik Graefenroda GmbH</td><td>8004-HP-H/i3&amp;micro;</td><td></td></tr><tr><td>pipette</td><td>Eppendorf</td><td>-</td><td></td></tr><tr><td>plastic vials</td><td>Sarstedt AG &amp;amp; Co.</td><td>6542.007</td><td></td></tr><tr><td>plastic vials</td><td>Greiner Bio-One International GmbH</td><td>717201</td><td></td></tr><tr><td>activimeter</td><td>MED Nuklear-Medizintechnik Dresden GmbH</td><td>-</td><td>Isomed 2010</td></tr><tr><td>tweezers</td><td></td><td>custom design</td><td></td></tr><tr><td>incubator</td><td>Heraeus Instruments GmbH</td><td>51008815</td><td></td></tr><tr><td>vortex mixer</td><td>Fisons</td><td>-</td><td>Whirlimixer</td></tr><tr><td>centrifuge</td><td>Heraeus Instruments GmbH</td><td>75003360</td><td></td></tr><tr><td>gamma well counter</td><td>MED Nuklear-Medizintechnik Dresden GmbH</td><td>-</td><td>Isomed 2100</td></tr><tr><td>water for chromatography</td><td>Merck KGaA</td><td>1.15333.2500</td><td></td></tr><tr><td>acetonitrile for chromatography</td><td>Merck KGaA</td><td>1.00030.2500</td><td></td></tr><tr><td>trifluoroacetic acid</td><td>Sigma-Aldrich</td><td>91707</td><td></td></tr><tr><td>TLC radioactivity scanner</td><td>raytest Isotopenmessger&amp;auml;te GmbH</td><td>B00003875</td><td>equipped with beta plastic detector</td></tr></tbody></table>

investigations on the ga(iii) complex of eob-dtpa and its 68ga radiolabeled analogue

我们证明为EOB-DTPA（3,6,9-三氮杂-3,6,9-三（羧甲基）-4-（乙氧基苄基）-undecanedioic酸）从其钆（III）络合物和协议的分离方法制备其的新的非放射性的， 即天然镓（Ⅲ），以及放射性68镓络合物。通过核磁共振（NMR）谱，质谱和元素分析复杂的配位体以及作为Ga（III）进行了表征。68嘎通过标准洗脱法从68锗/ 68 Ga产生获得。实验，以评估在pH值进行3.8-4.0 EOB-DTPA的68嘎标记效率。建立的分析技术无线电TLC（薄层色谱法）和无线电HPLC（高效液相色谱法）来测定示踪剂的放射化学纯度。由于68嘎示踪剂&#39;亲脂性正辛醇/水分布的第一个调查的存在于pH为7.4的溶液68镓物种n个系数是由萃取法在体外在生理pH下在各种媒体示踪剂的稳定性的测量进行测定。，揭示分解的不同的费率。

该配体EOB-DTPA和非放射性镓（III）络合物通过 1 H和13 C {1 1 H} NMR谱，质谱和元素分析进行分析。 表1中列出并描绘在图1-6的结果证实了物质的纯度。 68锗/ 68镓发生器洗脱，得到400-600活度68嘎的解决方案。在所需的示踪剂68镓[EOB-DTPA]形成所?...

Watch this Scientific Journal Video about Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue at JoVE.com

Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue

一种用于EOB-DTPA的分离和随后的络合天然镓（III）和68镓是本文中所呈现，以及所有化合物和调查上标记效率的透彻分析，体外稳定性和辛醇 /水过程放射性标记的复杂分配系数。

在EOB-DTPA和镓（三）复杂的调查其<sup&gt; 68</sup&gt;嘎放射性标记模拟

We demonstrate a method for the isolation of EOB-DTPA (3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(ethoxybenzyl)-undecanedioic acid) from its Gd(III) ...

investigations-on-ga-iii-complex-eob-dtpa-its-68ga-radiolabeled

Research

JoVE Journal

Chemistry

Investigations on the Ga(III) Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue

9.9K 次观看.  University Hospital Jena. 一种用于EOB-DTPA的分离和随后的络合天然镓（III）和68镓是本文中所呈现，以及所有化合物和调查上标记效率的透彻分析，体外稳定性和辛醇 /水过程放射性标记的复杂分配系数。 

视频: Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue

A Practical Guide for the Production and PET/CT Imaging of 68Ga-DOTATATE for Neuroendocrine Tumors in Daily Clinical Practice

Neuroendocrine tumors are a rare form of cancer that arise from neuroendocrine cells and can be present at almost any location throughout the body. Although heterogeneous in presentation, a common denominator among these tumors is the overexpression of somatostatin receptors. 68Ga-DOTATATE is a somatostatin analog labeled with the positron emitter gallium-68 (68Ga). For well-differentiated neuroendocrine tumors, 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) imaging is used for diagnosis, determination of disease burden, and therapy selection.
This protocol details the radiolabeling of 68Ga-DOTATATE, quality control, patient preparation, and subsequent PET/CT imaging. Radiolabeling of 68Ga-DOTATATE is performed with a fully automated labeling module coupled to a germanium-68 (68Ge)/68Ga generator. Quality control of the final product evaluates radiochemical purity with instant thin-layer chromatography and solid-phase chromatography, and pH prior to patient injection. Periodic quality control is performed to determine 68Ge breakthrough, sterility, and (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) content. Patient preparation includes patient instructions, a protocol for 68Ga-DOTATATE during treatment with somatostatin analogs, and intravenous administration of the radiopharmaceutical. For PET/CT imaging, the acquisition and reconstruction settings are described. For each step, radiation safety will be highlighted, as well as time constrictions due to the short half-life of 68Ga.
Fully automated in-house production and quality control of 68Ga-DOTATATE leads to very high success rates (95%) and produces two to four patient dosages per batch, depending on the yield of the generator. In conclusion, 68Ga-DOTATATE PET/CT imaging is a noninvasive and fast method of providing information on the tumor burden of neuroendocrine tumors (NETs) while also assisting in diagnosis and therapy selection.

A Practical Guide for the Production and PET/CT Imaging of 68Ga-DOTATATE for Neuroendocrine Tumors in Daily Clinical Practice

Well-differentiated neuroendocrine tumors overexpress somatostatin receptors which can be utilized for diagnostic imaging with the radiolabeled somatostatin analog 68Ga-DOTATATE. This protocol details the radiolabeling of 68Ga-DOTATATE, quality control, patient preparation, and subsequent PET/CT imaging. Radiation safety and time constrictions due to the short half-life of 68Ga are taken into account.

68型 Ga-DOTATATE 神经内分泌肿瘤的日常临床应用指南

Neuroendocrine tumors are a rare form of cancer that arise from neuroendocrine cells and can be present at almost any location throughout the body. ...

科研

癌症研究

Preparation and Evaluation of 99mTc-labeled Tridentate Chelates for Pre-targeting Using Bioorthogonal Chemistry

Pre-targeting combined with bioorthogonal chemistry is emerging as an effective way to create new radiopharmaceuticals. Of the methods available, the inverse electron demand Diels-Alder (IEDDA) cycloaddition between a radiolabeled tetrazines and trans-cyclooctene (TCO) linked to a biomolecule has proven to be a highly effective bioorthogonal approach to imaging specific biological targets. Despite the fact that technetium-99m remains the most widely used isotope in diagnostic nuclear medicine, there is a scarcity of methods for preparing 99mTc-labeled tetrazines. Herein we report the preparation of a family of tridentate-chelate-tetrazine derivatives and their Tc(I) complexes. These hitherto unknown compounds were radiolabeled with 99mTc using a microwave-assisted method in 31% to 83% radiochemical yield. The products are stable in saline and PBS and react rapidly with TCO derivatives in vitro. Their in vivo pre-targeting abilities were demonstrated using a TCO-bisphosphonate (TCO-BP) derivative that localizes to regions of active bone metabolism or injury. In murine studies, the 99mTc-tetrazines showed high activity concentrations in knees and shoulder joints, which was not observed when experiments were performed in the absence of TCO-BP. The overall uptake in non-target organs and pharmacokinetics varied greatly depending on the nature of the linker and polarity of the chelate.

Preparation and Evaluation of 99mTc-labeled Tridentate Chelates for Pre-targeting Using Bioorthogonal Chemistry

Here, we describe a protocol for radiolabeling and in vivo testing of tridentate 99mTc(I) chelate-tetrazine derivatives for pre-targeting and bioorthogonal chemistry.

制备和评价<sup&gt;99米</sup&gt;锝标记的三齿螯合物预靶向使用生物正交化学

Pre-targeting combined with bioorthogonal chemistry is emerging as an effective way to create new radiopharmaceuticals. Of the methods available, the ...

化学

Harnessing the Bioorthogonal Inverse Electron Demand Diels-Alder Cycloaddition for Pretargeted PET Imaging

Due to their exquisite affinity and specificity, antibodies have become extremely promising vectors for the delivery of radioisotopes to cancer cells for PET imaging. However, the necessity of labeling antibodies with radionuclides with long physical half-lives often results in high background radiation dose rates to non-target tissues. In order to circumvent this issue, we have employed a pretargeted PET imaging strategy based on the inverse electron demand Diels-Alder cycloaddition reaction. The methodology decouples the antibody from the radioactivity and thus exploits the positive characteristics of antibodies, while eschewing their pharmacokinetic drawbacks. The system is composed of four steps: (1) the injection of a mAb-trans-cyclooctene (TCO) conjugate; (2) a localization time period during which the antibody accumulates in the tumor and clears from the blood; (3) the injection of the radiolabeled tetrazine; and (4) the in vivo click ligation of the components followed by the clearance of excess radioligand. In the example presented in the work at hand, a 64Cu-NOTA-labeled tetrazine radioligand and a trans-cyclooctene-conjugated humanized antibody (huA33) were successfully used to delineate SW1222 colorectal cancer tumors with high tumor-to-background contrast. Further, the pretargeting methodology produces high quality images at only a fraction of the radiation dose to non-target tissue created by radioimmunoconjugates directly labeled with 64Cu or 89Zr. Ultimately, the modularity of this protocol is one of its greatest assets, as the trans-cyclooctene moiety can be appended to any non-internalizing antibody, and the tetrazine can be attached to a wide variety of radioisotopes.

The bioorthogonal inverse electron demand Diels-Alder cycloaddition has been harnessed to create an effective and modular pretargeted PET imaging strategy for cancer. In this protocol, the steps of this methodology are described in the context of a model system employing the colorectal cancer targeted antibody huA33 and a 64Cu-labeled radioligand.

利用生物正交反电子需求的Diels-Alder环的预靶向PET成像

Due to their exquisite affinity and specificity, antibodies have become extremely promising vectors for the delivery of radioisotopes to cancer cells for ...

生物工程

MR Molecular Imaging of Prostate Cancer with a Small Molecular CLT1 Peptide Targeted Contrast Agent

Tumor extracellular matrix has abundance of cancer related proteins that can be used as biomarkers for cancer molecular imaging. In this work, we demonstrated effective MR cancer molecular imaging with a small molecular peptide targeted Gd-DOTA monoamide complex as a targeted MRI contrast agent specific to clotted plasma proteins in tumor stroma. We performed the experiment of evaluating the effectiveness of the agent for non-invasive detection of prostate tumor with MRI in a mouse orthotopic PC-3 prostate cancer model. The targeted contrast agent was effective to produce significant tumor contrast enhancement at a low dose of 0.03 mmol Gd/kg. The peptide targeted MRI contrast agent is promising for MR molecular imaging of prostate tumor.

To demonstrate MR cancer molecular imaging with a small peptide targeted MRI contrast agent specific to clotted plasma proteins in tumor stroma in a mouse prostate cancer model.

前列腺癌与小分子肽CLT1靶向造影剂的磁共振分子成像

Tumor extracellular  matrix has abundance of cancer related proteins that can be used as biomarkers  for cancer molecular imaging. In this work,  we ...

医学

Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized cancer therapies in recent years. However, only a fraction of patients responds to PD-1/PD-L1 inhibitors, owing to the heterogeneous expression of PD-L1 in tumor cells. This heterogeneity presents a challenge in the precise detection of tumor cells by the commonly used immunohistochemistry (IHC) approach. This situation calls for better methods to stratify patients who will benefit from immune checkpoint blockade therapy, to improve treatment efficacy. Positron emission tomography (PET) enables real-time visualization of the whole-body PD-L1 expression in a noninvasive way. Therefore, there is a need for the development of radiolabeled tracers to detect PD-L1 distribution in tumors through PET imaging.
Compared to their L-counterparts, dextrorotary (D)-peptides have properties such as proteolytic resistance and remarkably prolonged metabolic half-lives. This study designed a new method to detect PD-L1 expression based on PET imaging of 68Ga-labeled PD-L1-targeted D-peptide, a D-dodecapeptide antagonist (DPA), in tumor-bearing mice. The results showed that the [68Ga]DPA can specifically bind to PD-L1-overexpressing tumors in vivo, and showed favorable stability as well as excellent imaging ability, suggesting that [68Ga]DPA-PET is a promising approach for the assessment of PD-L1 status in tumors.

Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

This study developed a noninvasive and real-time method to evaluate the distribution of programmed death-ligand 1 in the whole body, based on positron emission tomographic imaging of [68Ga] D-dodecapeptide antagonist. This technique has advantages over conventional immunohistochemistry and improves the efficiency of identifying appropriate patients who will benefit from immune checkpoint blockade therapy.

开发用于对程序性死亡配体 1 表达进行成像的 68镓标记的 D 肽 PET 示踪剂

The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized ...

<meta charset="utf8"></head><body>异种移植模型中 68个 Ga 标记纳米抗体的放射合成和 PET/CT 成像

Radiosynthesis, Quality Control, and Small Animal Positron Emission Tomography Imaging of 68Ga-Labelled Nano Molecules

Small animal Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging techniques are crucial in preclinical cancer research, necessitating meticulous attention to radiotracer synthesis, quality assurance, and in vivo injection protocols. This study presents a comprehensive workflow tailored to enhance the robustness and reproducibility of small animal PET experiments. The synthesis process in the radiochemistry laboratory using 68Ga is detailed, highlighting stringent quality control and assurance protocols for each radiotracer production. Parameters such as concentration, molar activity, pH, and purity are rigorously monitored, aligning with standards applicable to human studies. This methodology introduces streamlined syringe preparation and a custom-designed 30G cannula for precise intravenous injections into mice. Monitoring of animal health during scanning, including temperature and heart rate, ensures their well-being throughout the procedure. Dosages for PET and SPECT scans are predetermined to balance data acquisition with minimizing radiation exposure to animals and researchers. Similarly, CT scans employ pre-programmed settings to limit radiation exposure, especially pertinent in long-term studies assessing treatment effects. By optimizing these steps, the workflow aims to standardize procedures, reduce variability, and enhance the quality of small animal PET/SPECT/CT imaging. This resource provides valuable insights for researchers seeking to improve the accuracy and reliability of preclinical investigations in molecular imaging, ultimately advancing the field.

<meta charset="utf8"></head><body>68个 Ga-labeled Nano 分子的放射性合成、质量控制和小动物正电子发射断层扫描成像

This paper describes the radiosynthesis, formulation, quality control of a new radiolabeled probe (i.e., 68Ga-labeled nanobody NM-02), and its use for small animal PET/CT imaging in a xenograft model.

68个 Ga-labeled Nano 分子的放射性合成、质量控制和小动物正电子发射断层扫描成像

Small animal Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging techniques are crucial in preclinical ...

Automated Production of [68Ga]Ga-FAPI-46 on the iPHASE MultiSyn Synthesizer

An Automated Radiosynthesis of [68Ga]Ga-FAPI-46 for Routine Clinical Use

[68Ga]Ga-FAPI-46 is a promising new tracer for the imaging of fibroblast activation protein (FAP) by positron emission tomography (PET). Labeled FAP inhibitors (FAPIs) have demonstrated uptake in various types of cancers, including breast, lung, prostate, pancreatic and colorectal cancer. FAPI-PET also possesses a practical advantage over FDG-PET as fasting and resting are not required. [68Ga]Ga-FAPI-46 exhibits enhanced pharmacokinetic properties, improved tumor retention, and higher contrast images than the earlier presented [68Ga]Ga-FAPI-02 and [68Ga]Ga-FAPI-04. Although a manual synthesis protocol for [68Ga]Ga-FAPI-46 was initially described, in recent years, automated methods using different commercial synthesizers have been reported.
In this work, we describe the development of the automated synthesis of [68Ga]Ga-FAPI-46 using the iPHASE MultiSyn synthesizer for clinical applications. Initially, optimization of the reaction time and comparison of the performance of four different solid phase extraction (SPE) cartridges for final product purification were investigated. Then, the development and validation of the production of 0.6-1.7 GBq of [68Ga]Ga-FAPI-46 were conducted using these optimized parameters. The product was synthesized in 89.8 &#177; 4.8% decay corrected yield (n = 6) over 25 min. The final product met all recommended quality control specifications and was stable up to 3 h post synthesis.

This work describes the automated production of up to 1.7 GBq of [68Ga]Ga-FAPI-46 on the iPHASE MultiSyn synthesizer for PET imaging of fibroblast activation protein.

[68Ga]Ga-FAPI-46 is a promising new tracer for the imaging of fibroblast activation protein (FAP) by positron emission tomography (PET). Labeled FAP ...

Automated Preparation of [68Ga]Ga-3BP-3940 on a Synthesis Module for PET Imaging of the Tumor Microenvironment

A fast, efficient method has been developed on the GAIA synthesis module for automated gallium-68 radiolabeling of 3BP-3940, a molecular imaging probe targeting the fibroblast activation protein for positron emission tomography imaging of the tumor microenvironment. The reaction conditions involved acetate buffer (final concentration: 0.1 M), methionine as an anti-radiolysis agent (final concentration: 5.4 mg/mL), and 30 &#181;g of 3BP-3940, with heating for 8 min at 98 &#176;C. A final purification step on a C18 cartridge was necessary to obtain a radiolabeled product of high purity. In contrast, the generator-produced 68Ga was used directly without a concentration step on a cation exchange cartridge. The production of three validation batches confirmed the method&#39;s reliability, allowing the synthesis of [68Ga]Ga-3BP-3940 in 22.3 &#177; 0.6 min with high radiochemical purity (RCP), as determined by both radio-HPLC (99.1% &#177; 0.1%) and radio-TLC (99.2% &#177; 0.1%). The average radiochemical yield, based on RCP values measured by radio-HPLC, was 74.4% &#177; 3.3%. The stability of the radiolabeled product was demonstrated for up to 4 h after preparation. This protocol provides a reliable, rapid, and efficient methodology for the preparation of [68Ga]Ga-3BP-3940, which can easily be transposed to a clinical setting.

This research describes the automated process for [68Ga]Ga-3BP-3940 production with the GAIA V2 synthesizer, for PET imaging of fibroblast activation protein. The results of quality control tests performed on three test batches are also presented.

在合成模块上自动制备 [68Ga]Ga-3BP-3940，用于肿瘤微环境的 PET 成像

A fast, efficient method has been developed on the GAIA synthesis module for automated gallium-68 radiolabeling of 3BP-3940, a molecular imaging probe ...

在EOB-DTPA和镓（三）复杂的调查其

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此视频中的章节

⁶⁸型 Ga-DOTATATE 神经内分泌肿瘤的日常临床应用指南

制备和评价

利用生物正交反电子需求的Diels-Alder环的预靶向PET成像

前列腺癌与小分子肽CLT1靶向造影剂的磁共振分子成像

开发用于对程序性死亡配体 1 表达进行成像的 ⁶⁸镓标记的 D 肽 PET 示踪剂

⁶⁸个 Ga-labeled Nano 分子的放射性合成、质量控制和小动物正电子发射断层扫描成像

⁶⁸个 Ga-labeled Nano 分子的放射性合成、质量控制和小动物正电子发射断层扫描成像

⁶⁸个 Ga-labeled Nano 分子的放射性合成、质量控制和小动物正电子发射断层扫描成像

An Automated Radiosynthesis of [⁶⁸Ga]Ga-FAPI-46 for Routine Clinical Use

在合成模块上自动制备 [⁶⁸Ga]Ga-3BP-3940，用于肿瘤微环境的 PET 成像