CHARACTERIZATION OF OPIATE RECEPTOR USING POSITRON EMISSION TRANSAXIAL TOMOGRAPHY

使用正电子发射横轴断层扫描技术表征阿片受体

• 批准号: 3964162
• 负责人: K C RICE
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3964162
• 关键词: analgesics; autoradiography; brain imaging /visualization /scanning; brain mapping; chemical synthesis; drug design /synthesis /production; fluorine; high performance liquid chromatography; naloxone; naltrexone; narcotics; neuropharmacology; positron emission tomography; radiopharmacology; radiotracer; stereoisomer

We previously synthesized cyclofoxy, a fluoro analogue of the potent narcotic antagonist naltrexone, and showed the compound bound with high affinity to opiate receptors in vitro. This compound has now been tritiated to a specific activity of 16.4 Ci/mmol by mercuric oxide oxidation to the delta 15,16 dehydro derivative followed by palladium-catalysed reduction with carrier free tritium. Methodology has also been developed for synthesis of high specific activity 3-acetylcyclofoxy labeled with positron emitting [fluorine-18] for PETT imaging studies. The method utilizes reactor-produced [fluorine-18] as its tetraethylammonium (TEA-F) salt in a SN2 displacement on a secondary triflate precursor. Typically, 45% of the [fluorine-18] activity can be converted to the reactive TEAF in a 70 min preparation. From this, 35% yield (decay corrected) of the [fluorine-18] 3-acetylcyclofoxy was obtained after HPLC purification with a specific activity of 25 Ci/mmol in a total synthesis time of 60 min. [Fluorine-18] 3-acetylcyclofoxy accumulation in opiate receptor rich brain regions of both rat and baboon was shown to be completely displaced by the active enantiomer of naloxone ((-)-naloxone) while the identical dose of the pharmacologically inert (+)-naloxone has no detectable effect. Autoradiographic studies with tritiated cyclofoxy in rat brain slices have revealed that the compound labels a population of opiate receptors virtually identical to that labeled by naloxone. These and our previous results indicate that cyclofoxy is an excellent tool to study the physiological role of opiate receptors in living animals, and in humans using PETT imaging.

我们之前合成了 cyclofoxy，一种有效的氟类似物 麻醉拮抗剂纳曲酮，并显示该化合物与高浓度结合 体外对阿片受体的亲和力。 该化合物现已 通过氧化汞氚化至比活度为 16.4 Ci/mmol 氧化成 Delta 15,16 脱氢衍生物，然后 钯催化的无载流子氚还原。 还开发了用于合成高比活性的方法 3-乙酰基环氧基标记正电子发射 [氟-18] 用于 PETT 影像学研究。 该方法利用反应器产生的[氟18]作为其 二级SN2置换中的四乙铵（TEA-F）盐 三氟甲磺酸酯前体。 通常，45%的[氟18]活性可以是 在 70 分钟的准备过程中转化为反应性 TEAF。 由此看来，35% 获得[氟-18] 3-乙酰基环氧基的收率（衰减校正） HPLC纯化后总比活度为25 Ci/mmol 合成时间60分钟。 [Fluorine-18] 3-乙酰基环氧基积累 研究表明，大鼠和狒狒富含阿片受体的大脑区域 完全被纳洛酮活性对映体 ((-)-纳洛酮) 取代 而相同剂量的药理惰性（+）-纳洛酮则没有 可检测到的效果。 在大鼠脑切片中使用氚化环磷酰进行放射自显影研究 揭示该化合物标记了一群阿片受体 与纳洛酮标记的几乎相同。 这些和我们之前的 结果表明 cyclofoxy 是研究 阿片受体在活体动物和人类中的生理作用 使用PETT成像。