吲哚洛尔增强帕罗西汀对小鼠的抗抑郁作用

目前临床应用的几乎所有抗抑郁剂，包括一线用药选择性5-HT重摄取抑制剂（selective serotonin reuptake inhibitors，SSRIs），都存在起效延迟（显著起效需2～4周）和有效率不高（约75％）的问题。研究表明，5-HT1A受体拮抗剂可增强SSRIs的抗抑郁活性并缩短起效时间，这为新型药物的研发展示了诱人的前景。帕罗西汀（paroxetine）是SSRIs类抗抑郁剂中的典型代表。吲哚洛尔（pindolol）为β受体阻断药，主要用于治疗高血压、心律失常等疾病。有研究表明，吲哚洛尔也具有5-HT1A受体拮抗效应。     

5-羟色胺受体亚型mRNA在大鼠视网膜中的表达--RT-PCR法研究

目的 观察大鼠视网膜内5-羟色胺(5-HT)受体各种亚型mRNA的表达。方法 提取大鼠视网膜中的总RNA,用RT-PCR技术检测5-HT受体各种亚型mRNA的表达。将PCR产物进一步克隆人pCRⅡ载体,然后进行序列检测,测得的序列均与已知的各5-HT受体亚型的cDNA序列进行Blast比较。结果 5-HT受体亚型在阳性对照组中均呈阳性结果,各阳性条带的位置均与预期的各亚型PCR产物相符。经测序,证实产物确为预期的各5-HT受体亚型。RT-PCR结果显示,大鼠视网膜表达5-HT1A、5-HT2A、5-HT2C、5-HT3和5-HT7受体亚型,且以上各受体亚型阳性条带的密度存在着差异,以5-HT7和5-HT2a最高,5-HT2C和5-H3次之,而5-HT1A较弱。5-HT1B、5-HT1D、5-HT1E、5-HT1F、5-HT2b、5-HT4、5-HLA、5-HT5B和5-HT6受体亚型没有阳性条带。结论 大鼠视网膜上分布有多种5-HT受体亚型,包括5-HT1A、5-HT2A、5-HT2C、5-HT3和5-HT7。提示5-HT能系统可能普遍存在于哺乳动物视网膜中,且通过不同受体亚型在介导rod感光信号的过程中扮演着重要的角色。     

5-HT2A受体在腹外侧眶额皮质参与口面部疼痛的研究

目的 研究腹外侧眶额皮质5-HT2A受体表达水平对福尔马林诱导的口面部炎性痛发生的影响,揭示5-HT2A受体参与口面部疼痛的机制.方法 将6～8周龄C57BL雄性小鼠随机分为野生型组(WT组)、空载体组(NC组)、5-HT2A受体敲减组(KD组);腹外侧眶额皮质注射腺病毒建立小鼠5-HT2A受体敲减模型;4周后采用Western印迹法验证受体敲减效果;然后用微量注射器将30 μl1％福尔马林溶液(或生理盐水)注射到小鼠触须垫,记录45 min小鼠前、后爪摩擦触须垫时间.结果 Western印迹结果表明,KD组5-HT2A受体表达水平明显低于WT组和NC组,表明5-HT2A受体敲减成功.行为学结果表明在早期时相,福尔马林组小鼠摩擦触须垫的总时间无统计学差异,且均高于生理盐水组;在晚期时相,福尔马林组KD小鼠摩擦触须垫的总时间明显大于NC组和WT组,而WT组和NC组之间无统计学差异.结论 腹外侧眶额皮质5-HT2A受体可能在小鼠福尔马林炎性痛模型中通过影响晚期时相摩擦行为参与口面部疼痛调节.     

AT2受体对自发性高血压大鼠肾脏近曲小管上皮细胞AT1受体表达与功能的影响

目的 研究AT2受体激动剂CGP42112对自发性高血压大鼠(SHR)肾脏近曲小管上皮(RPT)细胞AT1受体的表达及功能的影响.方法 以RPT细胞株作为研究对象,采用不同浓度AT2受体激动剂CGP42t12(10-9～10-7mol/L)作用24h或同一浓度CGP42112(10-7mol/L)作用不同时间(8、16...     

运动对大鼠海马长时程增强效应及其相关因子的影响

目的:探讨运动对大鼠海马长时程增强(long-term potentiation,LTP)效应及其相关因子的影响。方法:28只成年雄性Wistar大鼠,随机分为对照组与运动组,每组14只。运动组采用4周自愿跑轮运动为体力运动模型。脑立体定位-神经电生理法检测海马齿状回LTP;高效液相-电化学法测定海马5-羟色胺(5-HT)含量;实时荧光定量PCR测定海马5-HT1A受体、环磷酸腺苷反应元件结合蛋白(CREB)和脑源性神经营养因子(BDNF)mRNA表达。结果:运动组海马齿状回LTP较对照组明显提高(P<0.05),运动组海马5-HT含量(P<0.01)、5-HT1A受体mRNA(P<0.01)、CREB和BDNF mRNA表达水平也显著高于对照组(P<0.05)。结论:运动可能通过对5-HT—5-HT1A受体—cAMP—CREB—BDNF—LTP通路元件的上调机制,发挥增强海马LTP的作用。     

脑缺血再灌注神经细胞血小板活化因子受体蛋白特性研究

目的探讨大鼠局灶性脑缺血再灌注后血小板活化因子(PAF)受体特性的变化。方法建立一侧大脑中动脉线栓闭塞再通模型，超速离心制备缺血脑皮质神经细胞突触膜和微粒体。采用放射配基结合实验，检测脑缺血再灌注后PAF受体的平衡解离常数(Kd)和最大结合数量(Bmax)。结果Scatchard作图分析显示，各组样本均存在3个特异性PAF结合位点，其中2个位于微粒体，另1个在突触膜上。单纯缺血90min时，突触膜位点Kd和Bmax明显减小；再灌注1d后，微粒体上2个位点的Kd、Bmax明显下降，至7d均未恢复到假手术组水平。结论缺血再灌注可诱导脑皮质神经细胞PAF受体下调，胞内受体下调晚发于突触膜受体。     

不同周期训练对大鼠脑纹状体5-HT含量及其代谢的影响

目的:观察不同周期训练对大鼠脑纹状体5-羟色胺(5-HT)含量及其代谢的影响,探讨纹状体5-HT代谢对运动性中枢疲劳影响的机理。方法:36只SD大鼠随机分为正常对照组(C)和2个训练组(T5和T7)。正常对照组自由活动。两训练组分别进行5周和7周游泳运动,第一周为适应性训练,最初运动时间为20分钟/天,每天递增10分钟,逐步延长至60分钟,并维持此量,每周连续训练5天。第二周起正式训练。最后一次训练后即刻断头处死,取全血测定外周色氨酸(Trp)含量,分离纹状体测定Trp、5-HT、5羟吲哚乙酸(5-HIAA)含量,色氨酸羟化酶(TPH)表达和单胺氧化酶(MAO)活性。结果:(1)与正常对照组相比,两训练组大鼠纹状体5-HT含量和MAO活性均有下降趋势;5周训练组纹状体Trp含量较高,7周训练组较低,但无统计学意义;5周血清Trp含量显著降低,7周显著升高;两组纹状体5-HIAA含量和TPH活性均显著升高(P<0.001)。(2)与5周训练组相比,7周训练组血清Trp和纹状体5-HIAA含量显著升高(P<0.01),纹状体TPH活性有升高趋势,而纹状体Trp、5-HT含量及MAO活性均有降低趋势。结论:无论是7周还是5周运动训练均可减少脑纹状体5-HT合成,加速其分解。这是长期训练后机体对运动的适应。运动训练周期长短可能是脑5-HT含量及其代谢的一个重要影响因素。     

模拟失重大鼠去内皮股动脉血管反应性的变化

目的　探讨模拟失重所致股动脉平滑肌反应性变化的特征与机制。　方法　通过尾部悬吊大鼠 4周模拟失重生理影响 ,利用离体去内皮股动脉血管环测定股动脉对血管活性物质的反应。　结果　模拟失重大鼠去内皮股动脉环对多种血管活性物质的收缩反应均明显降低。受体介导的股动脉收缩反应 ,如苯肾上腺素 ( 10 -6～ 10 -4mol/L)、内皮素 1( 10 -8～ 10 -7mol/L)及血管加压素 ( 10 -9～ 10 -7mol/L)诱发的收缩反应 ,在模拟失重 4周后均明显降低 ;非受体介导的收缩反应 ,如氯化钾( 4 0～ 80mmol/L)、氯化钙 ( 10 -5～ 5× 10 -3 mol/L)及钙离子载体A2 3187( 10 -6mol/L)激发的收缩反应在模拟失重 4周大鼠组亦明显较对照大鼠减弱。而去内皮股动脉环对硝普钠 ( 10 -9～ 10 -4mol/L)与环磷酸鸟苷 ( 10 -7～ 10 -3 mol/L)的舒张反应在模拟失重大鼠与对照大鼠间没有明显差别。去内皮股动脉对氯化钾、苯肾上腺素、血管加压素、内皮素 1、硝普钠与环磷酸鸟苷反应的敏感性在模拟失重大鼠与对照大鼠间亦没有明显差别。　结论　 4周模拟失重后大鼠去内皮股动脉受体介导与非受体介导的收缩反应均减弱 ,提示 4周模拟失重下股动脉平滑肌收缩装置的改变可能是造成股动脉反应性降低的主要因素     

5-HT1A受体显像剂99TcmO(MPMEP)(BMPDEEDA)的研究

目的　探讨研制99Tcm [N (2 (4 (2 甲氧基苯 ) 1 哌嗪 1 乙基 ) N (2 吡啶 ) 环己烷酰胺 ) ](WAY10 0 6 35 )类似物中枢神经系统 5 羟色胺 1A(5 HT1A)受体显像剂。方法　将化学合成的单齿配体 1 (2 甲氧基苯基 ) 4 (2 巯基乙基 )哌嗪 (MPMEP)和三齿配基N ,N 二 (2 巯基乙基 ) N′,N′ 二乙基乙二胺 (BMPDEEDA)与99Tcm 葡庚糖酸钠 (GH)经三齿配体与单齿配体混合标记方法 (“3+1”)混合配体交换 ,制得99TcmO(MPMEP) (BMPDEEDA)。同时 ,以大鼠脑海马膜组织匀浆为 5 HT1A 受体来源 ,与 5 HT1A受体的特异激动剂3H 2 (二 n 丙胺基 ) 8 羟基 四氢化萘 (8 OH DPAT)进行体外竞争结合实验 ,测定99Tcm 标记物的类似物ReO(MPMEP) (BMPDEEDA)对受体蛋白与特异拮抗 (激动 )剂竞争结合达到一半 (5 0 % )时的浓度 (IC50 值 )。结果　制备的99TcmO(MPMEP) (BMPDEEDA)经高压液相层析 (HPLC)纯化并测定其放化纯度 >95 %。大鼠脑海马摄取在注射后 30、6 0、12 0、180min时 %ID g分别为 0 .0 77、0 .0 6 8、0 .0 84和 0 .0 6 7,放射性摄取最高部位为丘脑 ,注射后 12 0min时 %ID g为 0 .15 4 ,各时相海马与小脑的摄取比值分别为 0 .84 7、0 .880、0 .92 1和 1.2 4 4。ReO(MPMEP) (BMPDEEDA)的IC50为 98.7     

胍丁胺在药物诱发抑郁模型上的药效评价

目的在药物诱发抑郁模型上观察胍丁胺(Agmatine,AG)的抗抑郁作用及可能的作用机制。方法采用小鼠5羟色胺酸(5hydroxytryptophan,5HTP)增强实验,小鼠育亨宾(yohimbine,YOH)毒性增强实验,小鼠阿朴吗啡(apomorphine,APO)诱导体温下降和利血平(reserpine,RES)诱导体温下降实验探讨AG抗抑郁作用及可能的作用环节。用VIDEOMEXV型图像运动解析仪检测小鼠自发活动行为。结果在小鼠5HTP增强实验模型上,单次ig给予AG10～20mg·kg-1剂量,或多次ig给予AG10～80mg·kg-1(qd,连续3d),对5HTP诱导的小鼠甩头行为均具有显著增强作用。在小鼠YOH毒性增强实验模型上,多次ig给予AG10～160mg·kg-1(qd,连续3d),均未见增强YOH毒性作用。在小鼠APO诱导体温下降实验模型上,ig给予AG10～80mg·kg-1(qd,连续7d),对APO16mg·kg-1诱导的降温和AUC0～30均未见显著性的拮抗作用。在小鼠RES诱导体温下降实验模型上,ig给予AG10～80mg·kg-1(qd,连续7d),对RES1mg·kg-1诱导的降温和AUC0～6均有显著的拮抗作用。小鼠ig给予AG10～80mg·kg-1(qd,连续3d)对自发活动无显著性改变。结论AG在药理学抑郁模型有显著的抗抑郁活性。并且其抗抑郁活性与增强5羟色胺(5HT)神经系统功能有关,而与去甲肾上腺素能(NE)神经功能无关。AG在抗抑郁有效剂量范围内无中枢兴奋或抑制性作用。     

以5-HT1A受体为靶标的抗抑郁药物研究进展

5-HT1A受体是含量最丰富的5-HT受体亚型,广泛分布于脑内,与抑郁症关系密切。抑郁症患者的5-HT1A受体表达异常,改变5-HT1A受体表达则影响抗抑郁治疗的效果;联合应用5-HT1A受体激动剂与选择性5-HT重摄取抑制剂（SSRIs）能够增强SSRIs的抗抑郁作用,缩短起效时间。近年研究发现,5-HT1A受体转录调控区C（-1019）G基因多态性与抑郁症的发病相关,并影响抗抑郁药物的效应。该文综述了5-HT1A受体在抑郁症发生和治疗中的作用及其作为药物研发新靶点的研究进展。     

5-HT_（1A）受体激动和5-HT重摄取抑制双靶标新药YL-0919抗抑郁作用的药效学评价

目的评价兼有5-HT1A受体激动和5-HT重摄取抑制双靶标化合物YL-0919的抗抑郁作用,并在靶标水平探讨其作用机制。方法和结果在小鼠悬尾和小鼠强迫游泳实验中,YL-0919（1.25,2.5,5 mg/kg,ig）能够显著地缩短小鼠悬尾不动时间和游泳不动时间,5-HT1A受体拮抗剂WAY100635（0.3 mg/kg,sc）能够完全拮抗YL-0919（2.5 mg/kg,ig）在小鼠悬尾实验中的抗抑郁作用;在药物诱发抑郁模型上,YL-0919增强5-羟色氨酸（5-hydroxytryptophan,5-HTP,120 mg/kg,ip）诱导的小鼠甩头行为,但不能拮抗高剂量阿扑吗啡（16 mg/kg,sc）诱导的降温作用;YL-0919在抗抑郁有效剂量范围内对小鼠的自主活动性无显著性影响。结论新型双靶标新药YL-0919具有明确的抗抑郁作用,此作用与激动5-HT1A受体,增强5-HT系统的功能有关。     

Psychopharmacology of 5-HT(1A) receptors

Serotonin(1A) (5-HT(1A)) receptors are located on both 5-HT cell bodies where they act as inhibitory autoreceptors and at postsynaptic sites where they mediate the effects of 5-HT released from nerve terminals. The sensitivity of 5-HT(1A) receptors in humans can be measured using the technique of pharmacological challenge. For example, acute administration of a selective 5-HT(1A) receptor agonist, such as ipsapirone, decreases body temperature and increases plasma cortisol through activation of pre- and postsynaptic 5-HT(1A) receptors, respectively. Use of this technique has demonstrated that unmedicated patients with major depression have decreased sensitivity of both pre- and postsynaptic 5-HT(1A) receptors. Treatment with selective serotonin reuptake inhibitors further down-regulates 5-HT(1A) receptor activity. Due to the hypotheses linking decreased sensitivity of 5-HT(1A) autoreceptors with the onset of antidepressant activity, there is current interest in the therapeutic efficacy of combined treatment with selective serotonin reuptake inhibitors and 5-HT(1A) receptor antagonists.     

抗抑郁剂对大鼠大脑皮层腺苷酸环化酶活性的影响

目的：观察３类抗抑郁剂对大鼠大脑皮层腺苷酸环化酶（ＡＣ）活性的影响,探讨药物的受体后作用机制。方法：提取大脑皮层突触膜,用现有的３类经典抗抑郁剂丙米嗪及阿米替林（三环类）、氟西汀（选择性５－ＨＴ重吸收抑制剂）、吗氯贝胺（单胺氧化酶抑制剂）与突触膜直接进行孵育,观察ＡＣ活性改变。结果：丙米嗪、阿米替林及氟西汀均可使ＡＣ激活,量效关系显著,而吗氯贝胺却无此作用,非抗抑郁剂苯丙胺（也是递质重吸收抑制剂）     

Positron emission tomography study of pindolol occupancy of 5-HT(1A) receptors in humans: preliminary analyses

Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT(1A) receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT(1A) antagonist [carbonyl-(11)C]WAY-100635 or [carbonyl-(11)C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexa necarboxamide abbreviated as [(11)C]WAY-100635. Pindolol dose-dependently decreased [(11)C]WAY-100635 BP. Combining all the regions, occupancy was 20 +/- 8% at scan 2, 14 +/- 8% at scan 3, and 44 +/- 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT(1A) receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT(1A) receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT(1A) autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT(1A) agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.     

Synthesis,biological and autoradiographic evaluation of a novel Tc-99m radioligand derived from WAY 100635 with high affinity for the 5-HT(1A) receptor and the alpha1-adrenergic receptor

This paper reports the synthesis, biological evaluation, in vitro and ex vivo autoradiography of the first Tc-99m ligand with subnanomolar affinity for the 5-HT(1A) receptor and a remarkably high affinity for the alpha1-adrenergic receptor. The neutral "3+1" mixed-ligand complex combines 4-(6-mercaptohexyl)-1-(2-methoxyphenyl)piperazine as monodentate and 3-(N-methyl)azapentane-1,5-dithiol as tridentate unit with oxotechnetium(V). The analogous rhenium complex was synthesized for complete structural characterization and used in receptor binding assays. In competition experiments both complexes display subnanomolar affinity for the 5-HT(1A) receptor (IC(50)0.24 nM for Re, 0.13 nM for Tc) but also very high affinities for the alpha1-adrenergic receptor (IC(50) 0.05 nM for Re, 0.03 nM for Tc). Biodistribution studies show a brain uptake in rat of 0.22% ID five minutes post injection. In vitro autoradiographic studies in rat brain and postmortem human brain indicate accumulation of the Tc-99m complex in brain areas which are rich in 5-HT(1A) receptors or in alpha1-adrenergic receptors. This in vitro enrichment can be blocked respectively by the 5-HT(1A) receptor agonist 8-OH-DPAT or by prazosin hydrochloride, an alpha1-adrenergic receptor antagonist. Ex vivo autoradiographic studies in rats show a slight accumulation of the Tc-99m complex in 5-HT(1A) receptor-rich areas of the brain, which could not be blocked, as well as in regions rich in alpha1-adrenergic receptors, which could be blocked by prazosin hydrochloride.     

25C-NBOMe short characterisation

Forensic Toxicology - N-Methoxybenzyls, a group of toxic phenylethylamine derivatives of the 2C family compounds, are a new class of potent serotonin 5-HT2A receptor agonist hallucinogens with...     

Serotonin-1A receptor imaging in recurrent depression: replication and literature review

INTRODUCTION: Serotonin-1A receptor (5-HT1AR) function appears to be decreased in major depressive disorder (MDD) based on physiological responses to 5-HT1AR agonists in vivo and to 5-HT1AR binding in brain tissues postmortem or antemortem. We have previously assessed 5-HT1AR binding potential (BP) in depression using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635, and we have demonstrated reduced 5-HT1AR BP in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders (n=12) versus controls (n=8) [Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375-87]. These findings were replicated by some, but not other, studies performed in depressed samples that were more generally selected using criteria for MDD. In the current study, we attempted to replicate our previous findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in our prior study. METHODS: Using PET and [carbonyl-(11)C]WAY-100635, 5-HT1AR BP was assessed in 16 depressed subjects and 8 healthy controls. RESULTS: Mean 5-HT1AR BP was reduced by 26% in the MTC (P<.005) and by 43% in the raphe (P<.001) in depressives versus controls. CONCLUSIONS: These data replicate our original findings, which showed that BP was reduced by 27% in the MTC (P<.025) and by 42% in the raphe (P<.02) in depression. The magnitudes of these reductions in 5-HT1AR binding were similar to those found postmortem in 5-HT1AR mRNA concentrations in the hippocampus in MDD [López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73] and in 5-HT1AR-binding capacity in the raphe in depressed suicide victims [Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001;25(6):892-903]. There exists disagreement within the literature, however, regarding the presence and direction of 5-HT1AR-binding abnormalities in depression, which may be explained in some cases by differences in anatomical location (e.g., [Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression--postmortem evidence for decreased serotonin activity. J Neurosci 1998;18(18):7394-401]) and in other cases by pathophysiological heterogeneity within MDD (e.g., some depressives hypersecrete cortisol, which would be expected to down-regulate 5-HT1AR expression [López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547-73]). Antidepressant drug treatment does not alter these abnormalities in 5-HT1AR binding [Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ. Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000;57(2):174-80; Moses-Kolko EL, Price JC, Thase ME, Meltzer CC, Kupfer DJ, Mathis CA, Bogers WD, Berman SR, Houck PR, Schneider TN, Drevets WC. Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635. Synapse 2007;61(7):523-30] but may compensate for blunted 5-HT1AR function by increasing post-synaptic 5-HT1AR transmission [Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991;5(4):219-29].     

Synthesis and biological evaluation of technetium(III) mixed-ligand complexes with high affinity for the cerebral 5-HT(1A) receptor and the alpha1-adrenergic receptor

Tc(III) and Re(III) complexes [M(NS(3))(CNR)] (M = Re, 99mTc, NS(3) = 2,2',2"-nitrilotris(ethanethiol), CNR = functionalized isocyanide bearing a derivative of WAY 100635) have been synthesized and characterized. Re was used as Tc surrogate for chemical characterization and in vitro receptor-binding studies. For two representatives subnanomolar affinities for the 5-HT(1A) as well as for the alpha1-adrenergic receptor were reached. Biodistribution studies in rats of the 99mTc complexes showed brain uptakes between 0.3 and 0.5% ID/organ (5 min p.i.). In vitro autoradiography of one 99mTc representative in sections of post mortem human brain indicate its accumulation in 5-HT(1A) receptor-rich brain regions. However, addition of the specific 5-HT(1A) receptor agonist 8-OH-DPAT as well as the alpha1-adrenoceptor antagonist prazosin could not substantially block this tracer accumulation. A preliminary SPET study in a monkey showed negligible brain uptake.     

Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system

The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY), p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET.