PET radiotracer development for imaging high-affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine-18 labeled aminotetralins in rodents.
PET radiotracer development for imaging high-affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine-18 labeled aminotetralins in rodents.
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用于对多巴胺 D2 和 D3 受体的高亲和力状态进行成像的 PET 放射性示踪剂开发：啮齿动物中氟 18 标记的氨基四氢化萘的结合研究。
DOI：
10.1002/syn.21950
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Pan,Min-Liang
中科院分区：
文献类型：
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作者：
Mukherjee,Jogeshwar;Majji,Divya;Kaur,Jasmeet;Constantinescu,CristianC;Narayanan,TanjoreK;Shi,Bingzhi;Nour,MohamedT;Pan,Min-Liang
在各种脑功能的PET成像研究中，多巴胺D2和D3受体的高亲和力，功能状态（HA）的成像已经被追求。我们进一步评价了18f‐5‐OH‐FPPAT，以及更新的18f‐5‐OH‐FHXPAT和18f‐7‐OH‐FHXPAT。18f‐5‐OH‐FHXPAT和18f‐7‐OH‐FHXPAT的合成通过修改我们先前报道的程序得到改进。雄性Sprague - Dawley大鼠的脑切片和脑匀浆与3种放射性示踪剂（74‐111 kBq/cc）一起使用。与多巴胺（1-100 nM）和Gpp(NH)p（10-50µM）竞争，以证明与多巴胺D2和D3的HA -状态结合，并测量18f - 5 - OH - FPPAT的结合动力学。对给予18f‐5‐OH‐FHXPAT的大鼠进行离体脑层自显影以确定HA‐状态结合。采用18f‐7‐OH‐FHXPAT（2‐37 MBq）对大鼠、野生型（WT）和D2敲除小鼠进行PET/CT成像。三种放射性示踪剂在脑切片上清晰地显示纹状体，多巴胺取代了80%以上的结合，18f - 5 - OH - FPPAT在匀浆中的解离率为2.2 × 10−2min−1。Gpp(NH)p处理显著降低了纹状体结合50-80%，且解离率更快（5.0 × 10−2min−1），表明18f‐5‐OH‐FPPAT和18f‐5‐OH‐FHXPAT的HA -状态结合。离体脑切片中18f - 5 - OH - FHXPAT的纹状体结合对Gpp(NH)p敏感，表明体内存在HA -状态结合。18f‐7‐OH‐FHXPAT在大鼠脑中的PET结合率为腹侧纹状体/小脑= 2.09，背侧纹状体/小脑= 1.65；在D2 WT小鼠中也发现了类似的结合比率。这些结果表明，大脑中激动剂的体内PET测量至少部分反映了多巴胺受体与膜结合的HA状态的结合。
Imaging the high‐affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of18F‐5‐OH‐FPPAT, and the newer18F‐5‐OH‐FHXPAT and18F‐7‐OH‐FHXPAT. Syntheses of18F‐5‐OH‐FHXPAT and18F‐7‐OH‐FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague‐Dawley rats were used with the 3 radiotracers (74‐111 kBq/cc). Competition with dopamine (1–100 nM) and Gpp(NH)p (10–50 µM) were carried out to demonstrate binding to dopamine D2 and D3 HA‐states and binding kinetics of18F‐5‐OH‐FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with18F‐5‐OH‐FHXPAT to ascertain HA‐state binding. PET/CT imaging in rats and wild type (WT) and D2 knock‐out mice were carried out using18F‐7‐OH‐FHXPAT (2‐37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10−2min−1for18F‐5‐OH‐FPPAT. Treatment with Gpp(NH)p significantly reduced 50–80% striatal binding with faster dissociation rates (5.0 × 10−2min−1), suggesting HA‐state binding of18F‐5‐OH‐FPPAT and18F‐5‐OH‐FHXPAT. Striatal binding of18F‐5‐OH‐FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA‐state binding in vivo. PET binding ratios of18F‐7‐OH‐FHXPAT in rat brain were ventral striatum/cerebellum = 2.09 and dorsal striatum/cerebellum = 1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane‐bound HA‐state of the dopamine receptor.