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神经内分泌肿瘤(neuroendocrine tumors,NETs)是一类起源于神经内分泌细胞的异质恶性肿瘤,分化良好的NETs可过度表达生长抑素受体(somatostatin receptor,SSTR)。奥曲肽、兰瑞肽等生长抑素类似物(somatostatin analogue,SSA)可与SSTR特异性结合。放射性核素标记的SSA可用于NETs的功能代谢显像,对疾病的早期诊断和精准定位具有重要意义。
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SSTR属于G蛋白偶联受体家族,共有5个亚型(SSTR1~5),以SSTR2最为常见[1]。奥曲肽、兰瑞肽和地普奥肽等是人工合成的SSTR激动剂,可与SSTR特异性结合,其中以奥曲肽的应用最为广泛。奥曲肽为八肽氨基酸序列,对SSTR具有较高的亲合力,尤其是SSTR2和SSTR5[2]。随着核医学分子影像技术的不断发展,不同放射性核素标记的SSA已得到成功研发,并应用于SPECT和PET的显像诊断(表1)。
SSA
类型显像
方式放射性
同位素生产方式 半衰期 衰变方式(%) 主要射线
能量(MeV)SSTR
显像剂首次临床试验
时间(年份)FDA
批准激动剂 SPECT 123I 回旋加速器 13.2 h EC 0.159 123I-Tyr3-OC[3] 1989 否 111In 回旋加速器 67.0 h EC 0.173 111In-DTPA-OC[4-6] 1992 是 99Tcm 99Mo-99Tcm发生器 6.02 h γ衰变 0.14 99Tcm-HYNIC-TOC[7] 2000 否 99Tcm-HYNIC-TATE[7] 2003 否 PET 68Ga 68Ge-68Ga发生器 68 min β+(89.1) 1.899 68Ga-DOTA-TATE [8-13] 2007 是 EC(10.9) 68Ga-DOTA-TOC[8-13] 2001 否 68Ga-DOTA-NOC[8-13] 2005 否 68Ga-DOTA-LAN[14-15] 2010 否 68Ga-DATA-TOC[16] 2019 否 64Cu 回旋加速器或反应堆 12.7 h β+(17.6) 0.653 64Cu-TETA-OC[17] 2001 否 EC(43.9) 64Cu-DOTA-TATE[18-20] 2012 否 β−(38.5) 64Cu-SAR-TATE[21-22] 2019 否 18F 回旋加速器 109.8 min β+(97) 0.635 18F-FP-Gluc-TOCA[23] 2003 否 EC(3) 18F-FET-βAG-TOCA[24-25] 2016 否 18F-AlF-NOTA-OC [26] 2019 否 18F-SiFAlin-TATE[27] 2020 否 44Sc 44Ti-44Sc发生器 3.97 h β+(94.27) 0.623 44Sc-DOTA-TOC[28] 2017 否 EC(5.73) 86Y 回旋加速器 14.7 h β+(31.9) 0.535 86Y-DOTA-TOC[29-30] 2001 否 EC(68.1) 拮抗剂 SPECT 111In 回旋加速器 67.0 h EC 0.173 111In-DOTA-BASS[31-33] 2011 否 PET 68Ga 68Ge-68Ga发生器 68 min β+(89.1) 1.899 68Ga-NODAGA-JR11[34-36] 2018 否 EC(10.9) 68Ga-DOTA-JR11[37] 2019 否 68Ga-NODAGA-LM3[38] 2021 否 68Ga-DOTA-LM3[38] 2021 否 注:SSTR为生长抑素受体;FDA为美国食品与药品监督管理局;SPECT为单光子发射计算机体层摄影术;PET为正电子发射断层显像术;β+为正电子;β−为负电子;EC为电子俘获;SSA为生长抑素类似物;OC为奥曲肽;Tyr3为酪氨酸3;DTPA为二亚乙基三胺五乙酸;HYNIC为肼基烟酰胺;DOTA为1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸;TOC为1-苯丙氨酸-酪氨酸3-奥曲肽;TATE为右旋-苯丙氨酸1-酪氨酸3-奥曲肽;NOC为萘丙氨酸1-奥曲肽;LAN为兰瑞肽;DATA为6-氨基-1,4-二氮杂三乙酸酯;TETA为1,4,8,11-四氮杂环十四烷-N,N′,N″,N′ ″-四乙酸;SAR为5-(8-甲基-3,6, 10,13,16,19-六氮杂-双环[6,6,6]二十烷-1-基氨基)-5-氧戊酸;18F-FP-Gluc-TOCA为α-N -(1-脱氧-D-果糖基)-Nε-(2-18F-氟丙酰基)-赖氨酸0-酪氨酸3-奥曲酸;18F-FET-βAG-TOCA为18F-氟乙基三唑-酪氨酸3-奥曲肽;18F-AlF-NOTA-OC为18F-Al-1, 4, 7-三氮杂环壬烷-1, 4, 7-三乙酸-奥曲肽;18F-SiFAlin-TATE为18F-对二叔丁基氟硅基-苯甲醛-奥曲肽;BASS为p-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH2;NODAGA为1,4,7-三氮杂环壬烷,1-戊二酸-4,7-乙酸;JR11为Cpa-c[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2;LM3为p-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2 表 1 放射性同位素标记的SSTR显像剂的分类及特征
Table 1. Classification and characteristics of radioisotope labeled somatostatin receptor imaging agents
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20世纪90年代初,111In 和123I标记的奥曲肽SSTR功能显像剂便已应用于临床[3]。111In-二亚乙基三胺五乙酸-奥曲肽(111In-diethylene-triaminepentaacetic acid-octreotide,111In-DTPA-OC)被美国食品与药品监督管理局(Food and Drug Administration,FDA)批准为NETs显像剂[4],是过去20年NETs功能显像的“金标准”显像剂[5]。以111In-DTPA-OC为显像剂的闪烁扫描显像技术(包括γ相机、SPECT、SPECT/CT)对NETs病灶均具有较高的检出率(50%~100%)[6]。虽然111In-DTPA-OC已广泛应用于NETs患者的诊断,但仍然存在一定的局限性:(1)111In的半衰期较长(67 h),导致辐射剂量较高;(2)111In发射的两种γ射线能量和丰度(0.173 MeV,89%和0.247 MeV,94%)相对较高,导致图像的空间分辨率降低;(3)111In-DTPA-OC在体内定位分布缓慢,耗费的时间成本较高[4]。
99Tcm-乙二胺N,N-二乙酸-酪氨酸3-奥曲肽[(99Tcm-ethylenediamine N, N-diacetic acid, EDDA)-Tyr3-octreotide,99Tcm-EDDA-TOC]、99Tcm-乙二胺N, N-肼基烟酰胺-酪氨酸3-奥曲肽[(99Tcm-ethylenediamine N, N-hydrazino-nicotinamide, HYNIC)-Tyr3-octreotide,99Tcm-HYNIC-TOC]和99Tcm-肼基烟酰胺-酪氨酸3-苏氨酸8-奥曲肽酸(99Tcm-HYNIC-Tyr3-Thr8- octreotade,99Tcm-HYNIC-TATE)的研发成功克服了111In-DTPA-OC的部分局限性。相较于111In-DTPA-OC,99Tcm-HYNIC-TOC具有更高的T/NT、更好的病灶定位能力和更高的诊断准确率,但受显像技术的影响,它对淋巴结和肝脏中长径<1 cm病变的检测能力仍然较差[7]。
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68Ga-SSA在NETs中的临床研究最为广泛,主要分为两大类。第一类是以1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid,DOTA)为螯合剂,如68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-苯丙氨酸1-酪氨酸3-奥曲肽(68Ga-DOTA-Phe1-Tyr3-OC,68Ga-DOTA-TOC)、68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-酪氨酸3-奥曲肽酸(68Ga-DOTA-Tyr3-octreotade,68Ga-DOTA-TATE)、68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-碘化钠3-奥曲肽(68Ga-DOTA-NaI3-OC,68Ga-DOTA-NOC)和68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸-兰瑞肽(68Ga-DOTA-lanreotide,68Ga-DOTA-LAN)。前三者已成为NETs SSTR显像的新标准显像剂[8],其中68Ga-DOTA-TATE已获美国FDA批准应用于临床[5],并被纳入NETs诊断的美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)指南[9]。该指南提出,68Ga-DOTA-TATE PET/CT可作为NETs初始诊断、原发肿瘤的定位以及肽受体放射性核素治疗(peptide receptor radionuclide therapy,PRRT)的首选方案[9]。
在肺、胃肠道和胰腺的NETs诊断方面,68Ga-DOTA-TATE与111In-DTPA-OC具有相似的特异度(93%),但是68Ga-DOTA-TATE的灵敏度和总体准确率均高于111In-DTPA-OC(分别为96% vs. 72%和94% vs. 84%)[10]。与99Tcm-HYNIC-OC相比,68Ga-DOTA-TATE对NETs病灶的诊断灵敏度更高(60% vs. 96%),并且可以发现更多胰腺、胃肠道及骨的转移病灶,假阴性率也相对更低[11]。68Ga-DOTA-TOC、 68Ga-DOTA-NOC 和68Ga-DOTA-TATE的配体均为奥曲肽衍生物,虽然3种显像剂对不同的SSTR亚型亲和力不同,但总体来说三者的诊断性能差异无统计学意义[12]。在NETs的初始诊断中,68Ga-DOTA-TOC、68Ga-DOTA-NOC、68Ga-DOTA-TATE PET显像的总体灵敏度为91%(95%CI,85%~94%)、特异度为94%(95%CI,86%~98%)。在分期和再分期中,68Ga-DOTA-TOC、68Ga-DOTA-NOC、68Ga-DOTA-TATE PET显像对原发或转移性病灶的诊断灵敏度为78.3%~100%、特异度为83%~100%[13]。68Ga-DOTA-LAN主要与SSTR3和SSTR4结合,与SSTR2的亲和力较低[14],而NETs以表达SSTR2为主。因此,68Ga-DOTA-LAN PET在NETs诊断和分期方面的价值不如68Ga-DOTA-TOC。对68Ga-DOTA-TOC摄取不佳或不摄取的NETs,可考虑选择68Ga-DOTA-LAN PET显像[15]。
另一类68Ga-SSA是以6-氨基-1,4-二氮杂三乙酸酯(6-amino-1,4-diazepine triacetate,DATA)为螯合剂,如68Ga-DATA-TOC。DATA是一种新型螯合剂,其与68Ga标记的SSTR显像剂结合具有更高的稳定性[16]。68Ga-DATA-TOC的合成更为简便、经济和高效,具有作为68Ga-DOTA-TOC有效安全替代品的潜力。
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64Cu作为一种半衰期长(12.7 h)、低正电子能量(Eβ+max=0.653 MeV)的放射性核素,在肿瘤显像和靶向治疗中的应用价值受到越来越多的关注。其最大正电子能量远低于68Ga(Eβ+max=1.899 MeV),可具有更高的PET空间分辨率。64Cu标记的SSA显像剂主要有3种,即64Cu-DOTA-TATE、64Cu-1,4,8,11-四氮杂环十四烷-N,N′,N″,N′″-四乙酸-奥曲肽(64Cu-1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N′″-tetraacetic acid-octreotide,64Cu-TETA-OC)和64Cu-5-(8-甲基-3,6, 10,13,16,19-六氮杂-双环[6,6,6]二十烷-1-基氨基)-5-氧戊酸-酪氨酸-奥曲肽[64Cu-5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6,6,6]icosan-1-ylamino)-5-oxopentanoic acid-Tyr3-OC,64Cu-SAR-TATE]。
临床初步试验结果显示,64Cu-TETA-OC的血液清除率和膀胱排泄率均较111In-DTPA-OC更高,且显像效果更好,可检测到更多NETs转移灶[17]。64Cu-DOTA-TATE和68Ga-DOTA-TOC的灵敏度相当,但64Cu-DOTA-TATE检测到病灶的真阳性率更高[18]。64Cu-DOTA-TATE注射后1 h和3 h的PET显像比较结果显示,两个时间点检测到的病灶数差异无统计学意义[19],较宽的显像时间窗提高了其用于NETs显像的便利性和灵活性。148 MBq(4.0 mCi)的64Cu-DOTA-TATE即可获得具有诊断质量的PET/CT显像,其灵敏度和特异度均较高(分别为100%和96.8%)[20]。该剂量可作为后续Ⅲ期临床研究的最佳注射剂量。64Cu-SAR复合物较64Cu-DOTA的生物性状更稳定[21],64Cu-SAR-TATE的临床试验结果表明,该显像剂具有良好的安全性[22]。其在注射后4 h或24 h的显像与68Ga-DOTA-TATE注射后1 h的显像相比,显示出的病灶数差异无统计学意义[22],这不仅提高了显像时间的灵活性,也增加了64Cu-SAR-TATE在核素治疗前多时间点剂量测定的可能性。
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已用于NETs临床研究的18F标记的氟化物主要有4类,包括18F-氟丙烯酸-4-硝基酯(18F-fluoropropionic acid-4-nitrophenyl ester,18F-FP)、18F-氟化铝 (18F-AlF2+)、18F-氟甲烷(18F-fluoroethane,18F-FEA)和18F-硅基氟化物(18F-silicon-based fluoride acceptor,18F-SiFA)。
Nα-(1-脱氧-D-果糖基)-Nε-(2-18F-氟丙酰基)-Lys0-Tyr3-奥曲肽酸[ Nα-(1-deoxy-D-fructosyl)-Nε-(2-18F-fluoropropionyl)-Lys0-Tyr3-octreotade,18F-FP-Gluc-TOCA]的肿瘤摄取及血液清除速率快,在注射时间(16±9) min和(34±12) min时,肿瘤与本底的比率分别高达80%和90%[23]。但由于18F-FP-Gluc-TOCA的合成过程复杂,制备时间较长(3 h),且放射化学产率有限(20%~30%),限制了其在临床中的应用。18F-氟乙基三唑-酪氨酸3-奥曲肽( 18F-fluoroethyltriazole-Tyr3-octreotide,18F-FET-βAG-TOCA)的临床研究结果已证实其安全性和人体可耐受性,在NETs转移的主要部位均显示出较高的肿瘤摄取以及T/NT[24]。与68Ga-DOTA-TATE相比,18F-FET-βAG-TOCA显像的灵敏度更高(92.8% vs. 87.5%)[25]。18F-Al-1, 4, 7-三氮杂环壬烷-1, 4, 7-三乙酸-奥曲肽( 18F-Al-1, 4, 7-triazacyclononane-1, 4, 7-triacetate-octreotide,18F-AlF-NOTA-OC)在NETs患者体内表现出良好的生物学分布特性、动力学特性和肿瘤靶向性,其肝脏生理性摄取低,可发现更多肝脏病变[26]。新型显像剂18F-对二叔丁基氟硅基-苯甲醛-奥曲肽酸[18F-p-(di-tert-butylfluorosilyl)benzaldehyde-octreotade,18F-SiFAlin-TATE]在人体内的生物学分布与68Ga-DOTA-TOC基本类似,大多数NETs病灶对18F-SiFAlin-TATE摄取较高,特别是NETs的常见转移部位对18F-SiFAlin-TATE的摄取均高于68Ga-DOTA-TOC,如肝脏(SUVmax:18.8±8.0 vs. 12.8±5.6)、淋巴结(SUVmax:23.8±20.7 vs. 17.4±16.1)和骨转移灶(SUVmax:16.0±10.1 vs. 10.3±5.7)[27]。18F-SSA的临床研究尚处于早期阶段,需要更多前瞻性Ⅱ/Ⅲ期临床研究检验其诊断性能。
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44Sc是用于PET显像的新型放射性核素,可通过回旋加速器大量获得,且其具有良好的物理性质(T1/2=3.97 h;Eβ+max=0.623 MeV)。44Sc-DOTA-TOC在临床试验中显示出良好的显像特性,延迟扫描可检测到非常小的病灶[28]。此外,47Sc是适用于核素治疗的放射性核素之一,44Sc标记的显像剂可与47Sc标记的治疗药物联合用于NETs的治疗前显像、治疗方案制定及疗效监测,实现NETs的诊疗一体化。但目前相关研究甚少,44Sc-SSA在NETs中的诊断价值还需更多的临床试验结果证实。
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90Y标记的SSA已用于NETs的临床治疗,但由于90Y是一种发射纯β-射线的核素,无法直接用于显像。以往多用111In-DTPA-OC进行90Y-SSA核素治疗前显像和剂量估算,但 111In-SSA与90Y-SSA在体内的生物学分布不同。理论上,86Y-SSA是90Y-SSA治疗前显像更为理想的显像剂。相较于111In-DTPA-OC SPECT,86Y-DOTA-TOC PET的图像质量更高,能更精确地估算90Y-SSA核素治疗所需剂量[29-30]。但86Y也存在一定的局限性,除β+射线外,86Y还发射0.628 MeV(32.6%)、0.703 MeV(15.4%)和1.077 MeV(82.5%)等多种额外的高能γ射线,导致显像背景噪音增强,空间分辨率降低,限制了其在临床中的实用性[29-30]。
生长抑素受体显像剂在神经内分泌肿瘤中的临床研究进展
Clinical research progress of somatostatin receptor imaging agents in neuroendocrine tumors
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摘要: 神经内分泌肿瘤(NETs)是一类起源于神经内分泌细胞的异质恶性肿瘤,分化良好的NETs可过度表达生长抑素受体(SSTR)。放射性同位素标记的生长抑素类似物与SSTR的特异性结合可实现NETs的功能成像,对NETs的诊断及其患者的临床管理具有重要意义。近年来,研究者已成功研发出多种靶向SSTR的示踪剂并应用于临床,笔者总结了用于SPECT和PET的SSTR显像剂在NETs中的临床应用及其研究进展。
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关键词:
- 神经内分泌瘤 /
- 受体,生长抑素 /
- 正电子发射断层显像术 /
- 体层摄影术,发射型计算机,单光子
Abstract: Neuroendocrine tumors (NETs) are a type of heterogeneous malignancies originating from the neuroendocrine system. Well-differentiated NETs can express high levels of somatostatin receptor (SSTR). Radioisotope-labeled somatostatin analogue can realize functional imaging in NETs by specifically binding to SSTR, which is crucial for the diagnosis and clinical management of NETs patients. In recent years, a variety of tracers targeting SSTR have been developed successfully, paving the avenue towards the precision medicine in NETs. The authors summarizs the development of SSTR imaging agents for SPECT or PET and their clinical applications in NETs. -
表 1 放射性同位素标记的SSTR显像剂的分类及特征
Table 1. Classification and characteristics of radioisotope labeled somatostatin receptor imaging agents
SSA
类型显像
方式放射性
同位素生产方式 半衰期 衰变方式(%) 主要射线
能量(MeV)SSTR
显像剂首次临床试验
时间(年份)FDA
批准激动剂 SPECT 123I 回旋加速器 13.2 h EC 0.159 123I-Tyr3-OC[3] 1989 否 111In 回旋加速器 67.0 h EC 0.173 111In-DTPA-OC[4-6] 1992 是 99Tcm 99Mo-99Tcm发生器 6.02 h γ衰变 0.14 99Tcm-HYNIC-TOC[7] 2000 否 99Tcm-HYNIC-TATE[7] 2003 否 PET 68Ga 68Ge-68Ga发生器 68 min β+(89.1) 1.899 68Ga-DOTA-TATE [8-13] 2007 是 EC(10.9) 68Ga-DOTA-TOC[8-13] 2001 否 68Ga-DOTA-NOC[8-13] 2005 否 68Ga-DOTA-LAN[14-15] 2010 否 68Ga-DATA-TOC[16] 2019 否 64Cu 回旋加速器或反应堆 12.7 h β+(17.6) 0.653 64Cu-TETA-OC[17] 2001 否 EC(43.9) 64Cu-DOTA-TATE[18-20] 2012 否 β−(38.5) 64Cu-SAR-TATE[21-22] 2019 否 18F 回旋加速器 109.8 min β+(97) 0.635 18F-FP-Gluc-TOCA[23] 2003 否 EC(3) 18F-FET-βAG-TOCA[24-25] 2016 否 18F-AlF-NOTA-OC [26] 2019 否 18F-SiFAlin-TATE[27] 2020 否 44Sc 44Ti-44Sc发生器 3.97 h β+(94.27) 0.623 44Sc-DOTA-TOC[28] 2017 否 EC(5.73) 86Y 回旋加速器 14.7 h β+(31.9) 0.535 86Y-DOTA-TOC[29-30] 2001 否 EC(68.1) 拮抗剂 SPECT 111In 回旋加速器 67.0 h EC 0.173 111In-DOTA-BASS[31-33] 2011 否 PET 68Ga 68Ge-68Ga发生器 68 min β+(89.1) 1.899 68Ga-NODAGA-JR11[34-36] 2018 否 EC(10.9) 68Ga-DOTA-JR11[37] 2019 否 68Ga-NODAGA-LM3[38] 2021 否 68Ga-DOTA-LM3[38] 2021 否 注:SSTR为生长抑素受体;FDA为美国食品与药品监督管理局;SPECT为单光子发射计算机体层摄影术;PET为正电子发射断层显像术;β+为正电子;β−为负电子;EC为电子俘获;SSA为生长抑素类似物;OC为奥曲肽;Tyr3为酪氨酸3;DTPA为二亚乙基三胺五乙酸;HYNIC为肼基烟酰胺;DOTA为1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸;TOC为1-苯丙氨酸-酪氨酸3-奥曲肽;TATE为右旋-苯丙氨酸1-酪氨酸3-奥曲肽;NOC为萘丙氨酸1-奥曲肽;LAN为兰瑞肽;DATA为6-氨基-1,4-二氮杂三乙酸酯;TETA为1,4,8,11-四氮杂环十四烷-N,N′,N″,N′ ″-四乙酸;SAR为5-(8-甲基-3,6, 10,13,16,19-六氮杂-双环[6,6,6]二十烷-1-基氨基)-5-氧戊酸;18F-FP-Gluc-TOCA为α-N -(1-脱氧-D-果糖基)-Nε-(2-18F-氟丙酰基)-赖氨酸0-酪氨酸3-奥曲酸;18F-FET-βAG-TOCA为18F-氟乙基三唑-酪氨酸3-奥曲肽;18F-AlF-NOTA-OC为18F-Al-1, 4, 7-三氮杂环壬烷-1, 4, 7-三乙酸-奥曲肽;18F-SiFAlin-TATE为18F-对二叔丁基氟硅基-苯甲醛-奥曲肽;BASS为p-NO2-Phe-cyclo(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)D-Tyr-NH2;NODAGA为1,4,7-三氮杂环壬烷,1-戊二酸-4,7-乙酸;JR11为Cpa-c[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH2;LM3为p-Cl-Phe-cyclo(D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys)D-Tyr-NH2 -
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