Lusaperidone   中文名称: 卢沙哌酮

α2A adrenergic receptor ( Ki = 0.13 nM ); α2C adrenergic receptor ( Ki = 0.15 nM )
- α₂-adrenoceptors (including hα₂A, hα₂B, hα₂C subtypes): R107474 has subnanomolar affinity for hα₂A-adrenoceptors (Ki = 0.13 nM) and hα₂C-adrenoceptors (Ki = 0.15 nM), nanomolar affinity for hα₂B-adrenoceptors (Ki = 1 nM) [1]
- 5-hydroxytryptamine₇ (h5-HT₇) receptors: R107474 shows nanomolar affinity (Ki = 5 nM) [1]
- Other receptors: R107474 interacts weakly with dopamine receptors (hD₂L, hD₃, hD₄) and other 5-HT subtypes (h5-HT₁D, h5-HT₁F, h5-HT₂A, h5-HT₂C, h5-HT₅A) with Ki values ranging from 81 to 920 nM [1]

Lusaperidone 对 α2A 和 α2C 肾上腺素受体具有亚纳摩尔亲和力（Ki 分别为 0.13 和 0.15 nM），对 hα2B 肾上腺素受体和 h5-HT7 受体具有纳摩尔亲和力（Ki 分别为 1 和 5 nM）。 Lusaperidone 与多巴胺-hD2L、-hD3 和 -hD4、h5-HT1D-、h5-HT1F-、h5-HT2A-、h5-HT2C- 和 h5-HT5A 受体相互作用较弱（Ki 值范围在 81 至 920 nM 之间）。卢沙哌酮经测试浓度高达 10 μM，仅在微摩尔浓度下与本研究中测试的任何其他受体或转运蛋白结合位点发生相互作用，或者根本不发生相互作用。卢沙哌酮已被证明可以逆转可乐定诱导的对细胞系中表达的人 α2A 和 α2C 肾上腺素受体（Kb 分别为 2.8 和 4.4 nM）介导的环 AMP 产生的抑制，并且是两种受体亚型的完全拮抗剂[1]。

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1. 受体结合实验：利用脑组织或表达克隆人受体的细胞制备膜制剂，检测R107474 对多种神经递质受体、药物受体、离子通道、肽受体及单胺转运体的结合抑制能力。当测试浓度高达10 μM时，R107474 仅与上述提及的受体（α₂-肾上腺素能受体、h5-HT₇受体、多巴胺受体及部分5-羟色胺亚型受体）发生相互作用，对其他测试受体/转运体无相互作用或仅在微摩尔浓度下发生相互作用 [1]

卢沙哌酮占据α2A和α2C肾上腺素能受体，ED50分别为0.014 mg/kg sc (0.009-0.019)和0.026 mg/kg sc (0.022-0.030)。 R107474体内静脉给药后的摄取非常迅速；在大多数组织（包括大脑）中，示踪剂注射后 5 分钟达到最大浓度[1]。

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1. α₂-肾上腺素能受体占据实验：动物皮下注射R107474 后，于给药1小时进行离体放射自显影，检测α₂A-和α₂C-肾上腺素能受体的占据情况。α₂A-肾上腺素能受体占据的ED₅₀（95%置信区间）为0.014 mg/kg 皮下注射（0.009–0.019），α₂C-肾上腺素能受体占据的ED₅₀（95%置信区间）为0.026 mg/kg 皮下注射（0.022–0.030）[1]
2. [¹¹C]R107474 在大鼠体内的生物分布：大鼠静脉注射[¹¹C]R107474 后，示踪剂在多数组织（包括大脑）中快速摄取，注射后5分钟达到最高浓度。大脑中放射性摄取最高的区域为隔区（注射后5分钟 3.54 ± 0.52 ID/g）和内嗅皮质（注射后5分钟 1.57 ± 0.10 ID/g）。隔区和内嗅皮质与小脑的浓度比随时间逐渐升高，注射后30分钟分别为5.38 ± 0.45和3.43 ± 0.24，这一现象源于示踪剂的快速摄取和缓慢洗脱 [1]
3. 体内阻断实验：将非选择性α₂-肾上腺素能受体拮抗剂米氮平与[¹¹C]R107474 联合给药，可特异性抑制[¹¹C]R107474 在大鼠大脑特定区域的结合 [1]

1. 受体结合实验流程：从脑组织或稳定表达克隆人受体（如α₂-肾上腺素能受体亚型、5-羟色胺受体、多巴胺受体）的细胞中制备膜制剂。将膜样品与不同浓度的R107474 及各靶受体对应的放射性标记配体共同孵育，孵育后分离未结合的放射性配体与膜结合的配体，通过检测结合部分的放射性强度，确定R107474 对配体-受体结合的抑制率，并根据抑制曲线计算Ki值，以评估R107474 对各受体的亲和力 [1]

1. α₂-肾上腺素能受体占据实验：给动物皮下注射不同剂量的R107474，给药1小时后处死动物，取出大脑并制备组织切片。对切片进行离体放射自显影，使用特异性放射性标记配体可视化并定量α₂A-和α₂C-肾上腺素能受体的占据情况 [1]
2. 大鼠生物分布实验：选用雄性Wistar大鼠，静脉注射[¹¹C]R107474。在注射后预设时间点（5、15、30、60分钟）处死大鼠，收集多种组织（包括隔区、内嗅皮质、小脑等大脑区域及其他外周组织），检测各组织样品的放射性强度，以每克组织注射剂量百分比（ID/g）表示摄取量 [1]
3. 体内阻断实验：大鼠在静脉注射[¹¹C]R107474 前预先给予非选择性α₂-肾上腺素能受体拮抗剂米氮平，指定时间后处死大鼠，收集大脑组织并检测特定区域[¹¹C]R107474 的放射性强度，与未预先给予米氮平的大鼠进行对比，计算结合抑制率 [1]

Rats: Male Wistar rats (weighing 200–250 g) are anesthetized with diethyl ether, and radiolabeled lusaperidone (24–28 GBq/μmol) is injected into their tail vein. The rats were given injections of 30–40 MBq in 300 μL saline containing 10% (v/v) ethanol at the beginning of the experiment. Under the influence of diethyl ether anesthesia, the rats are killed by cervical dislocation at 5, 10, 20, and 30 minutes after injection. After a cardiac puncture, a blood sample is obtained, and a few chosen tissues are quickly dissected and weighed. Radioactivity is quantified [1].

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1. α₂-adrenoceptor occupancy assay: Animals were administered R107474 via subcutaneous injection at different doses. One hour after administration, the animals were sacrificed, and their brains were removed and processed into tissue sections. Ex vivo autoradiography was performed on the sections using appropriate radiolabeled ligands to visualize and quantify α₂A- and α₂C-adrenoceptor occupancy [1]
2. Biodistribution assay in rats: Male Wistar rats were used for the experiment. [¹¹C]R107474 was administered to rats via intravenous injection. At predetermined time points (5, 15, 30, 60 minutes post-injection), the rats were sacrificed, and various tissues (including brain regions such as septum, entorhinal cortex, cerebellum, and other peripheral tissues) were collected. The radioactivity in each tissue sample was measured, and the uptake was expressed as percentage injected dose per gram of tissue (ID/g) [1]
3. In vivo blocking experiment: Rats were pre-administered mirtazapine (a non-selective α₂-adrenoceptor antagonist) before intravenous injection of [¹¹C]R107474. After the specified time, the rats were sacrificed, and brain tissues were collected to measure the radioactivity of [¹¹C]R107474 in selective brain regions. The binding inhibition rate was calculated by comparing with rats not pre-administered mirtazapine [1]

1. Tissue distribution: After intravenous administration of [¹¹C]R107474 in rats, the tracer was rapidly taken up by most tissues, with maximum concentration achieved at 5 minutes post-injection in the brain and other tissues. In the brain, the highest uptake was in the septum and entorhinal cortex, which is consistent with the known distribution of α₂-adrenoceptors. The tissue/cerebellum concentration ratios for septum and entorhinal cortex increased over time (up to 30 minutes post-injection) due to rapid uptake and slow washout [1]

[1]. Synthesis and biodistribution of [11C]R107474, a new radiolabeled alpha2-adrenoceptor antagonist. Bioorg Med Chem. 2006 Jul 1;14(13):4526-34.

1. R107474 is a potent and relatively selective α₂-adrenoceptor antagonist with the chemical structure 2-methyl-3-[2-(1,2,3,4-tetrahydrobenzo[4,5]furo[3,2-c]pyridin-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one [1]
2. [¹¹C]R107474 was synthesized via a Pictet-Spengler reaction with [¹¹C]formaldehyde, achieving an overall decay-corrected radiochemical yield of 33 ± 4%, a total synthesis time of 55 minutes, and a specific activity of 24–28 GBq/μmol [1]
3. [¹¹C]R107474 is a potential positron emission tomography (PET) ligand for studying central α₂-adrenoceptors due to its specific binding to α₂-adrenoceptors and favorable biodistribution characteristics in the brain [1]

C₂₂H₂₁N₃O₂

359.42

359.163

C, 73.52; H, 5.89; N, 11.69; O, 8.90

214548-46-6

3045401

White to light yellow solid powder

1.31g/cm3

538.3ºC at 760 mmHg

279.4ºC

1.17E-11mmHg at 25°C

1.688

3.287

50.75

0

4

3

27

751

0

O=C1C(CCN2CCC(OC3=CC=CC=C34)=C4C2)=C(C)N=C5N1C=CC=C5

ZYXHQIPQIKTEDI-UHFFFAOYSA-N

InChI=1S/C22H21N3O2/c1-15-16(22(26)25-11-5-4-8-21(25)23-15)9-12-24-13-10-20-18(14-24)17-6-2-3-7-19(17)27-20/h2-8,11H,9-10,12-14H2,1H3

3-[2-(3,4-dihydro-1H-[1]benzofuro[3,2-c]pyridin-2-yl)ethyl]-2-methylpyrido[1,2-a]pyrimidin-4-one

R107474; R-107474; R 107474

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~3.45 mg/mL (~9.6 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。