High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, 11C-TASP699
High-Contrast PET Imaging of Vasopressin V1B Receptors with a Novel Radioligand, 11C-TASP699
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DOI：
10.2967/jnumed.116.188698
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发表时间：
2017-10-01
影响因子：
9.3
通讯作者：
Higuchi, Makoto
中科院分区：
文献类型：
--
作者：
Koga, Kazumi;Nagai, Yuji;Higuchi, Makoto
加压素1B受体（V(1B)Rs）在垂体中大量表达，我们最近开发了一种特异性放射配体C-11-TASP0434299，衍生自pyridopy嘧啶-4-one，使V(1B)Rs的体内PET得以实现。在这里，我们发现了一种新的吡啶嘧啶-4- 1类似物，n-叔丁基-2-[2-（6- c -11-甲氧基吡啶-2-基）-6-[3（morpholin-4-基）丙氧基]-4-氧吡啶-[2,3-d]嘧啶-3(4H)-基]乙酰胺（C-11-TASP0410699，以下简称C-11-TASP699），作为一种有效的V1BR放射配体，比C-11-TASP0434299产生更高的图像对比度。方法：通过测定TASP699对人V1BR的亲和力和对脱靶分子的选择性来评价其体外特性。用PET分析了静脉注射C-11-TASP699后恒河猴垂体的放射性摄取。在放射配体注射前，连续给药2-[2-（3-氯-4-氟苯基）-6-[3-（morpholin-4-酰基）丙氧基]-4-氧吡啶[2,3-d]嘧啶-3（4H）酰基]- n-异丙基乙酰盐酸盐（TASP0390325）。使用或不使用非放射性V1BR拮抗剂，用C-11-TASP699对猴子垂体切片进行放射自显影标记。结果：TASP699对人V(1B)Rs的半数最大抑制浓度（IC50） （0.165 nM）低于TASP0434299 (0.526 nM)，而对脱靶分子的IC50值超过1 μ M.猴PET成像显示，C-11-TASP699的垂体摄取峰值与C-11-TASP0434299几乎相当，且TASP0390325预处理能以剂量依赖的方式抑制C-11-TASP699的保留，在0.3 mg/kg时几乎完全占据。在基线和阻断研究中，使用60分钟的放射性保留率，以平衡状态下的特定-不可置换摄取比来确定特异性放射性配体结合。C-11-TASP699的这一比率大约是C-11-TASP0434299的2.5倍。反相高效液相色谱研究鉴定了母体和极性放射性代谢物。2个预测的V(1B)Rs代谢物候选物的亲和性比亲本弱10倍以上。TASP0390325以浓度依赖的方式抑制C-11-TASP699对垂体前叶的强烈放射自显影标记。结论：C-11-TASP699比C-11-TASP0434299获得垂体V(1B)Rs的PET图像对比度更高，支持C-11-TASP699在神经精神疾病评估和临床试验中试验药物剂量发现方面的适用性。
Vasopressin 1B receptors (V(1B)Rs) are abundantly expressed in the pituitary, and in vivo PET of V(1B)Rs was recently enabled by our development of a specific radioligand, C-11-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4- one analog, N-tert-butyl-2-[2-(6-C-11-methoxypyridine-2-yl)-6-[3(morpholin-4-yl) propoxy]-4-oxopyrido[2,3-d] pyrimidin-3(4H)-yl] acetamide (C-11-TASP0410699, hereafter referred to as C-11-TASP699), as a potent V1BR radioligand producing a higher image contrast for the target than C-11-TASP0434299. Methods: In vitro properties of TASP699 were assessed by assaying its affinity for human V1BR and its selectivity for off-target molecules. Radioactive uptake in the pituitary was analyzed using PET in rhesus monkeys after intravenous administration of C-11-TASP699. Serial doses of a selective V1BR antagonist, 2-[2-(3-chloro-4-fluorophenyl)-6-[3-(morpholin-4-yl) propoxy]-4-oxopyrido[2,3-d] pyrimidin-3(4H)yl]- N-isopropylacetamide hydrochloride (TASP0390325), were administered before the radioligand injection. Autoradiographic labeling of monkey pituitary slices with C-11-TASP699 was conducted with or without nonradioactive V1BR antagonists. Results: The half maximal inhibitory concentration (IC50) of TASP699 for human V(1B)Rs (0.165 nM) was lower than that of TASP0434299 (0.526 nM), whereas its IC50 values for off-target molecules exceeded 1 mu M. PET imaging in monkeys demonstrated that the peak pituitary uptake of C-11-TASP699 was almost equivalent to that of C-11-TASP0434299 and that pretreatment with TASP0390325 inhibited the retention of C-11-TASP699 in a dose-dependent manner, inducing nearly full occupancy at 0.3 mg/kg. Specific radioligand binding was determined as a specific-to-nondisplaceable uptake ratio at equilibrium using radioactivity retentions at 60 min in baseline and blocking studies. This ratio for C-11-TASP699 was approximately 2.5-fold greater than that of C-11-TASP0434299. A reversed-phase high-performance liquid chromatography study identified the parent and polar radiometabolites. Affinities of 2 predicted metabolite candidates for V(1B)Rs were more than 10 times weaker than that of the parent. Intense autoradiographic labeling of the anterior pituitary with C-11-TASP699 was inhibited with TASP0390325 in a concentration-dependent manner. Conclusion: C-11-TASP699 yielded PET images of pituitary V(1B)Rs with a higher contrast than C-11-TASP0434299, supporting the applicability of C-11-TASP699 in the assessment of neuropsychiatric diseases and dose findings for test drugs in clinical trials.