Plisson Christophe, Gunn Roger N, Cunningham Vincent J, Bender Dirk, Salinas Cristian A, Medhurst Andrew D, Roberts Jennifer C, Laruelle Marc, Gee Antony D
GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, United Kingdom.
J Nucl Med. 2009 Dec;50(12):2064-72. doi: 10.2967/jnumed.109.062919. Epub 2009 Nov 12.
The histamine H(3) receptor is a G-protein-coupled presynaptic auto- and heteroreceptor whose activation leads to a decrease in the release of several neurotransmitters including histamine, acetycholine, noradrenaline, and dopamine. H(3) receptor antagonists such as 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) can increase the release of these neurotransmitters and thus may offer potential therapeutic benefits in diseases characterized by disturbances of neurotransmission. The aim of this study was to synthesize and evaluate (11)C-labeled GSK189254 ((11)C-GSK189254) for imaging the histamine H(3) receptor in vivo by PET.
GSK189254 exhibits high affinity (0.26 nM) and selectivity for the human histamine H(3) receptor. Autoradiography experiments were performed using (3)H-GSK189254 to evaluate its in vitro binding in porcine brain tissues. GSK189254 was labeled by N-alkylation using (11)C-methyl iodide in good yields, radiochemical purity, and specific activity. A series of PET experiments was conducted to investigate (11)C-GSK189254 binding in the porcine brain.
In vitro autoradiography demonstrated specific (3)H-GSK189254 binding in the porcine brain; therefore, (11)C-GSK189254 was evaluated in vivo in pigs and showed good brain penetration and high uptake in regions such as the striatum and cortices, known to contain high densities of the histamine H(3) receptors. The radioligand kinetics were reversible, and quantitative analysis was achieved with a 2-tissue-compartmental model yielding the distribution volume as the outcome measure of interest. The distribution volume was reduced to a homogeneous level in all regions after blocking by the coadministration of either unlabeled GSK189254 or ciproxifan, a structurally distinct histamine H(3) antagonist. Further coadministration studies allowed for the estimation of the radioligand affinity (0.1 nM) and the density of histamine H(3) receptor sites in the cerebellum (0.74 nM), cortex (2.05 nM), and striatum (2.65 nM).
These findings suggest that (11)C-GSK189254 possesses appropriate characteristics for the in vivo imaging of the histamine H(3) receptor by PET.
组胺H(3)受体是一种G蛋白偶联的突触前自身受体和异源受体，其激活会导致包括组胺、乙酰胆碱、去甲肾上腺素和多巴胺在内的多种神经递质释放减少。组胺H(3)受体拮抗剂，如6-[(3-环丁基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)氧基]-N-甲基-3-吡啶甲酰胺盐酸盐(GSK189254)，可增加这些神经递质的释放，因此可能在以神经传递紊乱为特征的疾病中提供潜在的治疗益处。本研究的目的是合成并评估(11)C标记的GSK189254((11)C-GSK189254)，用于通过正电子发射断层扫描(PET)在体内对组胺H(3)受体进行成像。
GSK189254对人组胺H(3)受体表现出高亲和力(0.26 nM)和选择性。使用(3)H-GSK189254进行放射自显影实验，以评估其在猪脑组织中的体外结合情况。通过用(11)C-甲基碘进行N-烷基化反应，以良好的产率、放射化学纯度和比活对GSK189254进行标记。进行了一系列PET实验，以研究(11)C-GSK189254在猪脑中 的结合情况。
体外放射自显影显示(3)H-GSK189254在猪脑中具有特异性结合；因此，对(11)C-GSK189254在猪体内进行了评估，结果显示其在脑中具有良好的穿透性，并且在已知含有高密度组胺H(3)受体的区域，如纹状体和皮质中摄取率较高。放射性配体动力学是可逆的，通过二组织室模型进行定量分析，得出分布容积作为感兴趣的结果测量指标。在共同给予未标记的GSK189254或西普司特（一种结构不同的组胺H(3)拮抗剂）进行阻断后，所有区域的分布容积均降至均匀水平。进一步的共同给药研究使得能够估计放射性配体亲和力(0.1 nM)以及小脑(0.74 nM)、皮质(2.05 nM)和纹状体(2.65 nM)中组胺H(3)受体位点的密度。
这些发现表明(11)C-GSK189254具有通过PET在体内对组胺H(3)受体进行成像的合适特性。
