N,N—二取代甘氨酸—3—羟基—1,4—苯并二氮卓酯制备方法的MNDO…

应用量子化学的微扰分子轨道理论，对用两种不同合成方法制备Ｎ，Ｎ－二取代甘氨酸－３－羟基－１，４－苯并二氮卓酯的可行性进行了分析。通过改进的忽略双原子微分重叠法（ＭＮＤＯ）程序计算，得到了原子净化电荷、前线轨道电荷及前线轨道系数，代入微扰分子轨道方程后，得到了半定量的理论产率估计，该估计与实验结果基本一致。     

电离辐射对NF－kB的影响

在简单介绍转录因子ＮＦ－ｋＢ的结构及功能的基础上，概述了电离辐射对ＮＦ－ｋＢ的影响及其机制，以期阐述辐射效应的分子机制。     

可见光照射N－甲基－N′－硝基－亚硝基胍在无H_2O_2下产生的羟基自由基

可见光照射Ｎ－甲基－Ｎ′－硝基－亚硝基胍在无Ｈ＿２Ｏ＿２下产生的羟基自由基［英］／ＭｉｋｕｎｉＴ…∥Ｒａ－ｄｉａｔＲｅｓ．－１９９４，１３８（３）－３２０～３２５为检验ＭＮＮＧ（Ｎ－甲基－Ｎ′－硝基－亚硝基胍）的致癌机制与产生的自由基有关，通过电子自...     

白血病中N－ras，H－ras，K－ras，Myc，Src和Sis高表达及其意义

白血病中Ｎ－ｒａｓ，Ｈ－ｒａｓ，Ｋ－ｒａｓ，Ｍｙｃ，Ｓｒｃ和Ｓｉｓ高表达及其意义＊＊本院青年科学基金资助课题（８９１２０４０）＊＊中国医学科学院基础医学研究所北京１００７３０董陆佳鲍家驹＊＊沈德愉＊＊贾蜀琼蒋本荣军事医学科学院附属医院北京１０００３９...     

5，8－二硫辛酸二乙氨基乙酯的合成、性质及其辐射防护作用

为了寻找稳定性好的辐射防护剂，探讨了５，８－二硫辛酸二乙氨基乙酯的合成、稳定性及其在小鼠上的抗辐射作用。实验证明，该化合物同硫辛酸（６，８－二硫辛酸）二乙氨基乙酯相比，化学稳定性明显增加，在实验室自然条件下长期放置，未发生聚合。该化合物具有较明显的辐射防护作用，照前腹腔注射给药。可使受致死剂量照射小鼠的活存率提高５６％－７０％；照后腹腔给药，也可使小鼠活存率提高４２．５％。     

利用杆状病毒早期启动子在昆虫细胞中持续表达人β－干扰素

在含苜蓿尺蠖核多角体病毒（ＡｃＮＰＶ）早期基因启动子的载体ｐＡｃＩＥ１中，插入人β－干扰囊（ＨｕＩＦＮ－β）基因，构建成转移载休ｐＩＥ１－ＩＢ；ｐＩＥ１－ＩＢ与含新霉素抗性基因（ＮＥＯ￣ｒ）的质粒ｐＩＥＩ－ＮＥＯ共转染秋粘虫细胞（Ｓｆ９细胞），使ＨｕＩＦＮ－β基因和ＮＥＯ￣ｒ基因整合到细胞基因组上产生转化细胞，含Ｇ４１８的培基分离新霉素抗性克隆，并增殖传代；转化细胞株传至５０代以上，不同传代水平细胞ＤＮＡ的点杂交证实ＨｕＩＦＮ－β基因已整合在细胞ＤＮＡ分子上，同时检测出干扰素（ＩＦＮ）的持续稳定表达，活性为５００—４０００ＩＵ／１０￣６细胞。抗天然ＨｕＩＦＮ－β抗体能完全中和所表达ＩＦＮ的抗病毒活性。     

人β－干扰素在杆状病毒载体与Sf细胞体系中的表达

采用苜蓿尺蠖核多角休病毒（Ａｕｔｏｇｒａｐｈａｃａｌｉｆｏｒｎｉｃａｎｕｃｌｅａｒｐｏｌｙｈｅｄｒｏｓｉｓｖｉｒｕｓ，ＡｃＮＰＶ）ＤＮＡ中多角体蛋白基因启动子及其前后序列作为转移载体，将人β－干扰素（ＨｕＩＦＮ－β基因插入转移载体ｐＵＡｃ－５，构建成ｐＡｃ－ＩＦＮ－β载体。该质粒ＤＮＡ与野生型ＡｃＮＰＶＤＮＡ经ｌｉｐｏｆｅｃｔｉｎ共转染秋粘虫（Ｓｐｏｄｏｐｔｅｒａｆｒｕｇｉｐｅｒｄａ）传代细胞（Ｓｆ９细胞），利用重组病毒不产生多角体蛋白的特征，进行病毒空斑筛选。用核酸杂交方法鉴定出携带ＨｕＩＦＮ－β基因的主组病毒。用重组病毒感染Ｓｆ９细胞，可表达ｒＨｕＩＦＮ－β。在１．０×１０￣６细胞／ｍｌ感染上清中测定ｒＨｕＩＦＮ－β最高活性为３．０×１０￣６ＩＵ／ｍｌ，抗天然ＨｕＩＦＮ－β抗体能完全中和ｒＨｕＩＦＮ－β的抗病毒活性。     

GMP－140与Ⅱ型糖尿病患者微血管病变关系的研究

目的：探讨α－颗粒膜蛋白（ＧＭＰ－１４０）与Ⅱ型糖尿病的关系，为临床诊断和治疗提供依据。方法：用放射免疫分析对１０４例（有微血管病变５５例，无微血管病变４９例）非胰岛素依赖性糖尿病（ＮＩＤＤＭ）患者和３８例健康人血小板ＧＭＰ－１４０、血浆ＧＭＰ－１４０进行测定及血小板直接计数。结果：ＮＩＤＤＭ患者血小板ＧＭＰ－１４０、血浆ＧＭＰ－１４０水平显著高于对照组（Ｐ＜０．００１）；有微血管病变ＮＩＤＤＭ与无微血管病变ＮＩＤＤＭ患者血小板ＧＭＰ－１４０、血浆ＧＭＰ－１４０水平比较差异有高度显著性（Ｐ＜０．００１）。有微血管病变和无微血管病变患者的血小板ＧＭＰ－１４０与血浆ＧＭＰ－１４０均呈显著正相关（ｒ１＝０．６９，ｒ２＝０．７５）；ＮＩＤＤＭ患者血小板计数与对照组比较差异无显著性（Ｐ＞０．０５）；ＮＩＤＤＭ患者在控制血糖（＜７．８ｍｍｏｌ／Ｌ）前提下服用阿斯匹林６个月后，复查眼底及ＧＭＰ－１４０，结果与治疗前无明显差异。结论：ＮＩＤＤＭ患者微血管病变与血小板功能及ＧＭＰ－１４０水平的变化有着十分密切的关系。     

垂直视动刺激下视－前庭功能的反应特点

在大视野的垂直视动刺激下，观察了２４名正常人的运动病症状、自身运动感觉－翻转错觉、垂直视动眼震（ＶＯＫＮ）、心电图Ｒ－Ｒ间隔功率谱的反应特点。垂直视动刺激由黑背景上随机分布的大小不等运动着的白色圆点的图象构成，视觉刺激是４种运动速度（３０、４５、６０、８０°／ｓ），两种垂直运动方向（上下）。电眼动图（ＥＯＧ）技术记录人的眼球运动。结果发现，向上方向运动的视动刺激诱发的ＶＯＫＮ平均慢相速度和增益比对向下方向运动的显著增大，两种运动方向的ＶＯＫＮ增益随视动速度增加而减少。４５～８０°／ｓ垂直视动刺激下翻转错觉有方向性不对称。不同的垂直视动速度刺激引起运动病的症状不同，４５°／ｓ时诱发的运动病最大。垂直视动刺激中心率和Ｒ－Ｒ间隔功率谱没有显著变化，而前庭刺激（平行秋千６ｍ，３．９５ｍ／ｓ２）下，引起的心率、Ｒ－Ｒ间隔功率谱Ｃ波显著增加。根据视－前庭相互作用调制理论讨论了ＶＯＫＮ和翻转错觉的不对称性，提出视前庭功能的不对称可能是空间运动病的致病因素的一种。     

α－颗粒膜蛋白与糖尿病血管病变关系的研究

用放免法对５６例非胰岛素依懒型糖尿病（ＮＩＤＤＭ）患者和３８例健康人进行血小板和血浆α－颗粒膜蛋白（简称ＧＭＰ－１４０）测定。结果表明ＮＩＤＤＭ患者血小板和血浆ＧＭＰ－１４０水平明显高于对照组（Ｐ＜０．００１），差异极显著，而糖尿病合并微血管病变组的血小板和血浆ＧＭＰ－１４０的水平又明显高于无微血管病变组（Ｐ＜０．００１）。提示ＮＩＤＤＭ患者的血管并发症尤其是微血管病变与血小板的功能改变有着密切的关系。     

利用菌落免疫荧光法鉴定对多种支原体起反应的单克隆抗体

我们用菌落免疫荧光染色技术对4株(3D_1、3A_(11)、3F_5、2E_5)抗精氨酸支原体(MycoPlasma arginini)McAb进行了鉴定,在热水固定的菌落上3D_1、3A_(11)不仅与精氨酸支原体出现了阳性反应,而且与口腔支原体(M.orale)、猪鼻支原体(M.hyorhinis)、莱氏无胆甾原体(AcholePlasma laidlawii)、羊无乳支原体(M.agalactia)PG_2和牛丝状支原体丝状亚种(M.mycoides subsp. mycoides)PG_1等均有交叉反应;在未固定的菌落上用表面免疫荧光检测时, McAb却表现了与PcAb不同的特性。同时我们还做了阻断试验,进一步证明了我们制备的McAb的支原体特异性。     

A new 18F-labeled fluoroacetylmorpholino derivative of vesamicol for neuroimaging of the vesicular acetylcholine transporter

With the aim of producing selective radiotracers for in vivo imaging of the vesicular acetylcholine transporter (VAChT) using positron mission tomography (PET), here, we report synthesis and analysis of a new class of conformationally constrained vesamicol analogues with moderate lipophilicity. The sequential ring opening on trans-1,4-cyclohexadiene dioxide enabled an approach to synthesize 6-arylpiperidino-octahydrobenzo[1,4]oxazine-7-ols [morpholino vesamicols]. The radiosynthesis of the [18F]fluoroacetyl-substituted derivative ([18F]FAMV) was achieved starting from a corresponding bromo precursor [2-Bromo-1-[7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazin-4-yl]-ethanone] and using a modified commercial computer-controlled module system with a radiochemical yield of 27+/-4%, a high radiochemical purity (99%) and a specific activity of 35 GBq/micromol. In competitive binding assays using a PC12 cell line overexpressing VAChT and [3H]-(-) vesamicol, 2-fluoro-1-[7-hydroxy-6-(4-phenyl-piperidin-1-yl)-octahydro-benzo[1,4]oxazin-4-yl]-ethanone (FAMV) demonstrated a high selectivity for binding to VAChT (K(i): 39.9+/-5.9 nM) when compared to its binding to sigma 1/2 receptors (Ki>1500 nM). The compound showed a moderate lipophilicity (logD (pH 7)=1.9) and a plasma protein binding of 49%. The brain uptake of [18F]FAMV was about 0.1% injected dose per gram at 5 min after injection and decreased continuously with time. Notably, an increasing accumulation of radioactivity in the lateral brain ventricles was observed. After 1 h, the accumulation of [18F]FAMV, expressed as ratio to the cerebellum, was 4.5 for the striatum, 2.0 for the cortical and 1.5 for the hippocampal regions, measured on brain slices using ex vivo autoradiography. At the present time, 75% of [18F]FAMV in the plasma was shown to be metabolized to various hydrophilic compounds, as detected by high-performance liquid chromatography. The degradation of [18F]FAMV was also detected in brain extracts as early as 15 min post injection (p.i.) and increased to 50% at 1 h postinjection. In conclusion, although the chemical properties of [18F]FAMV and the selectivity of binding to VAChT appear to be promising indicators of a useful PET tracer for imaging VAChT, a low brain extraction, in combination with only moderate specific accumulation in cholinergic brain regions and an insufficient in vivo stability prevents the application of this compound for neuroimaging in humans.     

Aurora激酶抑制剂ZM447439的合成及生物活性研究

目的优化Aurora激酶抑制剂ZM447439的合成路线,并对其体外生物活性进行评价。方法以4-羟基-3-甲氧基苯甲酸为起始原料,通过酯化、取代、硝化、还原、关环等反应合成ZM447439,涉及到的中间体及目标产物结构经1H-NMR,MS及IR确证。以MTT法研究其体外抗肿瘤活性(U937,K562,A549,LoVo及HT29细胞株),同时评价其体外AuroraA/B激酶抑制活性。结果合成了Aurora A/B激酶抑制剂ZM447439并进行相关生物活性研究。结论新合成路线总收率约34%,目标化合物具有较好的Aurora A/B激酶活性及肿瘤细胞增殖抑制活性。     

以京尼平交联制备新型人工神经支架材料及其生物学特性的对比研究

目的 从超微结构、孔隙率、溶胀率、降解率、交联度及细胞毒性等方面分别比较紫外线、京尼平及戊二醛交联后的壳聚糖复合Ⅰ型胶原蛋白人工神经支架材料的生物学特性. 方法 (1)材料按交联方法不同分为三组:紫外线组、京尼平组、戊二醛组.(2)经扫描电镜观察三组材料内部结构的排列规律及走形,测量其孔径大小、计算孔隙率及孔径分布等指标.(3)溶胀率与体外降解率:三组材料交联完后立即称重(W_0),然后在培养皿中加入10 ml无菌PBS,24 h后用无菌滤纸擦干水分称重(W_1).溶胀率(%)=(W_1-W_0)/W_0×100%.剩余材料于4,8,12周分别取出后称重(W_2).降解率(%)=(W_1-W_2)/W_1×100%.(4)检测交联度:每组取10根材料,其中5根加入碳酸氢钠和三硝基苯磺酸(TNBS),再加盐酸,在346 nm测吸光度(A)值(A_(三硝基苯磺酸)).另外5根先加盐酸,然后再加TNBS,其余步骤相同,测得吸光度取平均值作为对照(A_对),交联后吸光度值为:A_(交联后)=A_(三硝基苯磺酸)-A_(对).再取一组10根未交联过的材料,以同样步骤测吸光度,得到交联前吸光度(A_(交联前)).交联度=(A_(交联前)-A_(交联后))/A_(交联前)×100%.(5)细胞毒性试验:遵照GB/T16886/ISO 10993医疗器械生物学评价之体外细胞毒性试验原则,采用国际标准的两种试验方法,选用建系的L929小鼠成纤维细胞对改性后的支架材料进行体外细胞毒性试验. 结果 (1)未交联的材料为均匀圆柱状,内部为孔径均匀且平行排列的微观结构,其微孔直径为30～120 μm;交联后紫外线组孔径基本不变,京尼平、戊二醛两组孔径均变小.(2)京尼平和戊二醛组孔隙率差异无统计学意义,两者都要高于紫外线组;而溶胀率京尼平组高于戊二醛组,戊二醛组又高于紫外线组.(3)京尼平和戊二醛两组的交联度分别为55.3%和82.5%.(4)京尼平和戊二醛组在PBS中浸泡4,8,12周,体外降解率差异无统计学意义;而紫外线组材料降解明显高于前两者.(5)戊二醛组浸提液培养的细胞出现部分坏死现象,相反京尼平和紫外线组细胞生长良好. 结论 以京尼平交联壳聚糖复合Ⅰ型胶原蛋白制备出改进的人工神经支架,具有良好的生物稳定性和生物相容性,为神经组织工程领域提供了一种具有应用潜力的材料.     

Evaluation of a bromine-76-labeled progestin 16alpha,17alpha-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies

INTRODUCTION: Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy. METHOD: 16alpha,17alpha-[(R)-1'-alpha-(5-[(76)Br]Bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione ([(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (3)), a PR ligand with relative binding affinity (RBA)=65 and log P(o/w)=5.09+/-0.84, was synthesized via a two-step reaction, and its tissue biodistribution and metabolic stability were evaluated in estrogen-primed immature female Sprague-Dawley rats. RESULTS: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was synthesized in 5% overall yield with specific activity being 200-1250 Ci/mmol. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 demonstrated high PR-mediated uptake in the target tissue uterus (8.72+/-1.84 %ID/g at 1 h) that was reduced by a blocking dose of unlabeled progestin R5020, but the nonspecific uptake in blood and muscle (2.11+/-0.14 and 0.89+/-0.16 %ID/g at 1 h, respectively) was relatively high. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was stable in whole rat blood in vitro, but it was not stable in vivo due to the fast metabolism that occurred in the liver, resulting in the formation of a more polar radioactive metabolite and free [(76)Br]bromide. The level of free [(76)Br]bromide in blood remained high during the experiment (2.11+/-0.14 %ID/g at 1 h and 1.52+/-0.24 %ID/g at 24 h). The tissue distribution of [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 at 1 and 3 h was compared with that of the (18)F analogs, [(18)F]FFNP fluoro furanyl norprogesterone (FFNP) 1 and ketal 2. CONCLUSION: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 may have potential for imaging PR-positive breast tumors at early time points, but it is not suitable for imaging at later times or for radiotherapy.     

Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation

To develop a radiopharmaceutical for the palliation of painful bone metastases based on the concept of bifunctional radiopharmaceuticals, we synthesized a bisphosphonate derivative labeled with rhenium-186 (186Re) that contains a hydroxyl group at the central carbon of its bisphosphonate structure, we attached a stable 186Re-MAMA chelate to the amino group of a 4-amino butylidene-bisphosphonate derivative [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-HBP) and we investigated the effect of a hydroxyl group at the central carbon of its bisphosphonate structure on affinity for hydroxyapatite and on biodistribution by conducting a comparative study with [N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-BP). The precursor of 186Re-MAMA-HBP, trityl (Tr)-MAMA-HBP, was obtained by coupling a Tr-MAMA derivative to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. 186Re-MAMA-HBP was prepared by a reaction with 186ReO(4-) and SnCl2 in citrate buffer after the deprotection of the Tr groups of Tr-MAMA-HBP. After reversed-phase high-performance liquid chromatography, 186Re-MAMA-HBP had a radiochemical purity of over 95%. Compared with 186Re-MAMA-BP, 186Re-MAMA-HBP showed a greater affinity for hydroxyapatite beads in vitro and accumulated a significantly higher level in the femur in vivo. Thus, the introduction of a hydroxyl group into 186Re complex-conjugated bisphosphonates would be effective in enhancing accumulation in bones. These findings provide useful information on the design of bone-seeking therapeutic radiopharmaceuticals.     

Synthesis of fluorine-18-labeled ciprofloxacin for PET studies in humans

Ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid), a widely-prescribed antibiotic, was labeled with fluorine-18 with the aim to perform positron emission tomography studies in humans for pharmacokinetic measurements. Due to a lack of chemical activation of ciprofloxacin for a direct nucleophilic exchange reaction a novel two-step synthetic approach, which employed an activated 6-fluoro-7-chloro substituted precursor molecule, was developed. The radiosynthesis yielded, starting from 52.5 +/- 11.3 GBq of [(18)F]fluoride, 1.3 +/- 0.6 GBq (n = 13) [(18)F]ciprofloxacin ready for intravenous administration in about 130 min synthesis time. A series of analytical tests was performed in order to prove the identity of the radiolabeled compound and its suitability for human applications.     

Monitored arterial and end-tidal carbon dioxide during in-flight mechanical ventilation

Introduction: Mechanical ventilation with monitored arterial carbon dioxide tension is necessary for optimum pulmonary support and hemodynamic stability. Ongoing monitoring is necessary to ensure adequate ventilation parameters. The prospective study purpose was to (1) compare mechanical ventilation to historic manual ventilation, (2) evaluate the effectiveness of institutional tidal volume parameters, (3) determine the effect of institutional tidal volume manipulation on end-tidal carbon dioxide tension, and (4) explore the relationship between in-flight end-tidal carbon dioxide tension and arterial carbon dioxide tension.

Methods: Randomized groups were mechanically ventilated (tidal VOLUME = 12 cc/kg, RATE = 14/min) with a target arterial carbon dioxide tension between 30 and 35 torr. Group I was monitored with in-line end-tidal carbon dioxide tension, and group II was monitored with arterial carbon dioxide tension by means of inflight arterial blood gas.

Results: Arterial carbon dioxide tension varied less with monitored mechanical than with manual ventilation (p = 0.001). The gradient between arterial and end-tidal carbon dioxide tension was 5.3 ± 4.4 (mean ± standard deviation [SD]). End-tidal and arterial carbon dioxide tension positively correlated (r = 0.76, P = 0.001), yet end-tidal carbon dioxide tension accounted for only 58% variation of arterial carbon dioxide tension (r² = 0.58).

Conclusion: Mechanical ventilation is more precise but inconsistent in achieving a target arterial carbon dioxide tension with current ventilation parameters. End-tidal carbon dioxide tension is a reasonable estimate of, but cannot exclusively replace, arterial carbon dioxide tension in critically ill patients.     

C-(4-[18F]fluorophenyl)-N-phenyl nitrone: A novel 18F-labeled building block for metal free [3+2]cycloaddition

Radiofluorination via [3+2]-nitrone-alkene cycloaddition was studied using the model reaction between (18)F-labeled C-(4-fluorophenyl)-N-phenyl nitrone ([(18)F]1) and substituted maleimides 2a-c. [(18)F]1 was prepared in RCY of 73.6±5.8% and radiochemical purity of >95%. Cycloaddition of [(18)F]1 to 2a in toluene at 80°C and in EtOH at 110°C gave the respective isoxazolidine [(18)F]5a in >80% RCY at 10min reaction time. Reaction between [(18)F]1 and 2b, c also went smoothly to afford the respective cycloaddition products in high radiochemical yields.     

Evaluation of 18F-FA-4 and 11C-pipzA-4 as radioligands for the in vivo evaluation of the high-affinity choline uptake system.

4,4'-Bis-1-hydroxy-2-(4-methylpiperidin-1-yl)ethyl-biphenyl (A-4), a tertiary amine analog of hemicholinium-3 (HC-3), is an inhibitor of the sodium-dependent high-affinity choline uptake (HACU) system. We have evaluated 4-[1-hydroxy-2-(4-(18)F-fluoromethylpiperidin-1-yl)ethyl]-4'-[1-hydroxy-2-(4-methylpiperidin-1-yl)ethyl]biphenyl ((18)F-FA-4) and 4-[1-hydroxy-2-(4-(11)C-methylpiperazin-1-yl)ethyl]-4'-[1-hydroxy-2-(4-methylpiperidin-1-yl)ethyl]biphenyl ((11)C-pipzA-4), an (18)F- and a (11)C-labeled derivative of A-4 as potential in vivo tracers for the HACU system. METHODS: The biodistribution of both compounds was determined in mice, and the intracerebral distribution was visualized by ex vivo and in vitro autoradiography. The in vitro affinity of the compounds was determined by a displacement study with (3)H-HC-3 on mice brain slices. RESULTS: In mice, both tracers show a high and persistent brain uptake. In vitro autoradiography shows binding to the striatum, whereas ex vivo autoradiography shows homogeneous binding throughout the brain. FA-4 and pipzA-4 inhibited the (3)H-HC-3 binding with a 50% inhibitory concentration of 57 nmol/L and 320 nmol/L, respectively. CONCLUSION: The evaluated compounds have affinity for HACU and show high uptake in the brain. In vitro binding of the compounds to the striatum cannot be inhibited by the presence of HC-3, whereas binding of HC-3 was inhibited by the presence of both FA-4 and pipzA-4, suggesting allosteric binding.