Cardiac hypoxia imaging: second-generation analogues of 64Cu-ATSM.
Cardiac hypoxia imaging: second-generation analogues of 64Cu-ATSM.
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DOI：
10.2967/jnumed.113.129015
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Southworth R
中科院分区：
文献类型：
--
作者：
Handley MG;Medina RA;Mariotti E;Kenny GD;Shaw KP;Yan R;Eykyn TR;Blower PJ;Southworth R
心肌缺氧是诊断和预后成像的一个有吸引力的靶点，但目前的方法对于临床应用还不够敏感。PET示踪剂铜(II)-二乙酰-双(N4-甲基氨基硫脲)(64Cu-ATSM)具有很好的应用前景，但其选择性和灵敏度可以通过结构修饰来提高。因此，我们评估了一系列用于乏氧心肌成像的64Cu-ATSM类似物。在自制的三重γ检测系统中，分离的大鼠心脏(n=5/组)先用常氧缓冲液灌流30min，然后用低氧缓冲液灌流45min，以定量放射性示踪剂的输注、低氧依赖的心脏摄取和洗脱。在常氧、低氧早期和晚期动脉内注射1-MBq剂量的每个候选示踪剂(和18F-氟咪唑作为对照)，评价它们的低氧选择性和药代动力学。然后，通过PET成像和生物分布来评估有前景的候选药物在健康大鼠体内的药代动力学。所有被测试的类似物在5分钟内都表现出对缺氧的敏感性。亲油性低于64Cu-ATSM的络合物在低氧-常氧对照中有显著的提高(64Cu-2，3-丁二酮双缩氨基硫脲(ATS)14：1，64Cu-2，3-戊二酮双(缩氨基硫脲)(CTS)17：1，64Cu-ATSM 8：1，P<；0.05)。低氧首过摄取率分别为78.2%±7.2%和70.7%±14.5%，而64Cu-ATS为63.9%±11.7%。18F-氟异硝唑的心脏滞留率从常氧时的0.44%±0.17%增加到低氧时的2.24%±0.08%。在体内，64Cu-CTS的常氧心脏滞留显著低于64Cu-ATSM和64Cu-ATS(0.13%±0.02%vs.0.25%±0.04%和0.24%±0.03%注射剂量，P<；0.05)，3种示踪剂在6分钟内的滞留均低于0.7%注射剂量。64CuCTS在肝脏和肺中的摄取也较低。与现有的铅低氧示踪剂64Cu-ATSM和18F-氟咪唑相比，64Cu-ATS和64Cu-CTS具有更好的心脏低氧选择性和影像特征。
Myocardial hypoxia is an attractive target for diagnostic and prognostic imaging, but current approaches are insufficiently sensitive for clinical use. The PET tracer copper(II)-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM) has promise, but its selectivity and sensitivity could be improved by structural modification. We have therefore evaluated a range of 64Cu-ATSM analogs for imaging hypoxic myocardium. Isolated rat hearts (n = 5/group) were perfused with normoxic buffer for 30 min and then hypoxic buffer for 45 min within a custom-built triple-γ-detector system to quantify radiotracer infusion, hypoxia-dependent cardiac uptake, and washout. A 1-MBq bolus of each candidate tracer (and 18F-fluoromisonidazole for comparative purposes) was injected into the arterial line during normoxia, and during early and late hypoxia, and their hypoxia selectivity and pharmacokinetics were evaluated. The in vivo pharmacokinetics of promising candidates in healthy rats were then assessed by PET imaging and biodistribution. All tested analogs exhibited hypoxia sensitivity within 5 min. Complexes less lipophilic than 64Cu-ATSM provided significant gains in hypoxic-to-normoxic contrast (14:1 for 64Cu-2,3-butanedione bis(thiosemicarbazone) (ATS), 17:1 for 64Cu-2,3-pentanedione bis(thiosemicarbazone) (CTS), 8:1 for 64Cu-ATSM, P < 0.05). Hypoxic first-pass uptake was 78.2% ± 7.2% for 64Cu-ATS and 70.7% ± 14.5% for 64Cu-CTS, compared with 63.9% ± 11.7% for 64Cu-ATSM. Cardiac retention of 18F-fluoromisonidazole increased from 0.44% ± 0.17% during normoxia to 2.24% ± 0.08% during hypoxia. In vivo, normoxic cardiac retention of 64Cu-CTS was significantly lower than that of 64Cu-ATSM and 64Cu-ATS (0.13% ± 0.02% vs. 0.25% ± 0.04% and 0.24% ± 0.03% injected dose, P < 0.05), with retention of all 3 tracers falling to less than 0.7% injected dose within 6 min. 64Cu-CTS also exhibited lower uptake in liver and lung. 64Cu-ATS and 64Cu-CTS exhibit better cardiac hypoxia selectivity and imaging characteristics than the current lead hypoxia tracers, 64Cu-ATSM and 18F-fluoromisonidazole.
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影响因子：
3.1
作者：
Oh, SJ;Chi, DY;Moon, DH
通讯作者：
Moon, DH
影响因子：
3.1
作者：
Dearling, Jason L. J.;Packard, Alan B.
通讯作者：
Packard, Alan B.
影响因子：
4.9
作者：
Dearling, JLJ;Lewis, JS;Blower, PJ
通讯作者：
Blower, PJ
影响因子：
3.1
作者：
Dence, Carmen S.;Ponde, Datta E.;Lewis, Jason S.
通讯作者：
Lewis, Jason S.
DOI：
10.1007/s002590050283
发表时间：
1998-07-01
期刊：
EUROPEAN JOURNAL OF NUCLEAR MEDICINE
影响因子：
--
作者：
Dearling, JLJ;Lewis, JS;Blower, PJ
通讯作者：
Blower, PJ