Reaching out for Sensitive Evaluation of the Mu Opioid Receptor in Vivo: Positron Emission Tomography Imaging of the Agonist [11C]AH7921.
Reaching out for Sensitive Evaluation of the Mu Opioid Receptor in Vivo: Positron Emission Tomography Imaging of the Agonist [11C]AH7921.
复制标题
对体内 Mu 阿片受体进行灵敏评估：激动剂 [11C]AH7921 的正电子发射断层扫描成像。
作者：
Waqas Rafique;S. Khanapur;Mona M Spilhaug;P. Riss
用正电子发射断层扫描(PET)技术对Mu阿片受体(MOR)的可用性进行成像是神经科学领域的一项相关挑战。内源性阿片类物质对受体表达和占位的调节都与健康功能和疾病的认知和行为表型有关。分别使用高亲和力放射激动剂和放射拮抗剂PET示踪剂可以测量活跃和非活跃状态下的受体表达。占位评估要求放射性配基具有竞争性和可逆性，与MOR具有中等亲和力，这可能导致体内受体特异性信号的物理消退。我们在大鼠身上研究了一种中等效力、选择性的MOR激动剂，以测试为与内源性阿片类药物竞争而量身定做的放射性示踪剂设计范例是否会导致可行的成像结果。合成了苯甲酰胺-3，4-二氯苯甲酸(二甲氨基)环己基甲酰胺(AH-7921，1)，并用放射自显影和正电子发射断层扫描对其进行了表征。化合物1被发现以低纳摩尔效力激活MOR，并在较小程度上激活KOR作为完全激动剂。通过与激动剂和拮抗剂放射性配基的浓度依赖性结合研究来评估竞争行为，并获得抑制常数。3，4-二氯苯[11C]羧酸(二甲氨基)环己基甲酰胺与大鼠脑内结合的动力学分析表明，丘脑的结合电位较低，但可重复性较好(0.8±0.1)。在脑中检测到放射性代谢物(15min后为17%)。尽管如此，我们得出结论，当使用中等亲和力的放射性示踪剂时，定量成像MOR的可用性是可能的。
Imaging of the mu opioid receptor (MOR) availability with positron emission tomography (PET) is a pertinent challenge in Neuroscience. Both, regulation of receptor expression and occupancy by endogeneous opioids play into cognitive and behavioral phenotypes of healthy function and disease. Receptor expression in the active and inactive states can be measured using high affinity radioagonist and radioantagonist PET tracers, respectively. Occupancy assessment requires radioligands showing competitive and reversible binding with moderate affinity to the MOR, which may lead to physical extinction of the receptor specific signal in vivo. We investigated a moderately potent, selective MOR agonist in rat to test if a radiotracer design paradigm tailored to competition with endogeneous opioids leads to viable imaging results. The benzamide 3,4-dichlorobenzenecarboxylic acid (dimethylamino)cyclohexyl)methyl amide (AH-7921, 1) was synthesized and characterized in rat brain using autoradiography and positron emission tomography. Compound 1 was found to activate with low nanomolar potency the MOR and to a lesser extent KOR as a full agonist. Concentration dependent binding studies with agonist and antagonist radioligands were conducted to assess competition behavior and obtain inhibition constants. Kinetic analysis of 3,4-dichlorobenzene[11C]carboxylic acid (dimethylamino)cyclohexyl)methyl amide binding in rat brain resulted in low but reproducible binding potential in the thalamus (0.8 ± 0.1). A radioactive metabolite was detected in brain (17%, after 15 min). Nonetheless, we conclude that quantitative imaging of MOR availability is possible when using a moderate affinity radiotracer.