Efficient preparation and biological evaluation of a novel multivalency bifunctional chelator for 64Cu radiopharmaceuticals.
Efficient preparation and biological evaluation of a novel multivalency bifunctional chelator for 64Cu radiopharmaceuticals.
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DOI：
10.1002/chem.201101894
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发表时间：
2011-09-05
期刊：
影响因子：
--
通讯作者：
Conti PS
中科院分区：
文献类型：
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作者：
Liu S;Li Z;Yap LP;Huang CW;Park R;Conti PS
正电子发射断层扫描（PET）是一种功能强大的成像技术，可提供有关放射性标记生物分子分布的体内信息。例如，2-脱氧-2-18 F-氟-D-葡萄糖（18 F-FDG）已成功地使PET成为癌症诊断、患者分层和监测癌症患者治疗的常规临床实践。[1]PET的发展取决于新的放射性示踪剂的开发，这些示踪剂将补充18F-FDG。尽管PET核素11C（t1/2 = 20.4 min）和18F（t1/2 = 109.7 min）已被广泛用于PET成像探针的开发，但它们的短半衰期为评价具有长体内循环时间的生物活性配体设置了强烈的限制。64 Cu（t1/2 = 12.7 h）通过β +（20%）和β −发射（37%）以及电子捕获（43%）衰变，使其非常适合放射性标记蛋白质，抗体和肽，用于PET成像（β +）和治疗（β +和β −）。[2]低β +能量还保证了PET图像中低至1 mm的良好分辨率，并保证了成像扫描期间对患者的最小辐射剂量。[3]由于直接将64 Cu加入靶向配体（如肽和抗体）中是不切实际的，因此已经投入了大量的努力来开发64 Cu的双功能螯合剂（BFC）。目前，1，4，7，10-四氮杂环十二烷-N，N '，N "，N""-四乙酸（DOTA）是用于64 Cu标记的最广泛使用的螯合剂之一。然而，其适度的体内稳定性会增加非靶器官辐射剂量并降低肿瘤与非肿瘤的对比度。[4，5]已报道具有改进的稳定性的~（64）Cu标记的放射性药物，包括1，4，7-三氮杂环壬烷-1，4，7-三乙酸（NOTA）衍生物，[6 - 7]交联的1，4，8，11-四氮杂环十四烷-1，4，8，11-四乙酸（CB-TETA），[5，8]和1，4，8，11-四氮杂双环[6.6. 2]十六烷（CB-TE2A）衍生物。[9 - 11]对于这些BFC，64Cu螯合通常需要相对苛刻的条件，例如高温。最近，一种新型的BFC已经被
Positron emission tomography (PET) is a powerful imaging technique that provides in vivo information on the distribution of radiolabeled biomolecules. For example, 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG) has successfully made PET a routine clinical practice in cancer diagnose, patient stratification, and monitoring the treatment of cancer patients.[1] The advancement of PET depends on the development of new radiotracers that will complement 18F-FDG. Although PET nuclides 11C (t1/2= 20.4 min) and 18F (t1/2= 109.7 min) have been widely used for the development of PET imaging probes, their short halflives set a strong limitation for evaluating bioactive ligands with long in vivo circulation time. 64Cu (t1/2= 12.7 h) decays by β+(20%) and β− emission (37%), as well as electron capture (43%), making it well suited for radiolabeling proteins, antibodies and peptides, both for PET imaging (β+) and therapy (β+ and β−).[2] The low β+-energy also promises a good resolution of down to 1 mm in PET images and guarantees minimal radiation doses to the patients during imaging scans.[3]Because direct addition of 64Cu into a targeting ligand (such as peptides and antibodies) is not practical, significant efforts have been devoted to the development of bifunctional chelators (BFCs) for 64Cu. Currently, 1, 4, 7, 10-tetra-azacyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) is one of the most widely used chelators for 64Cu labeling. However, its moderate in vivo stability would increase the non-targeted organ radiation dosage and lower the tumor-to-nontumor contrast.[4, 5] 64Cu-Labeled radiopharma-ceuticals with improved stability have been reported including 1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA) derivatives,[6–7] cross-bridged 1, 4, 8, 11-tetraazacyclotetradecane-1, 4, 8, 11-tetraacetic acid (CB-TETA),[5, 8] and 1, 4, 8, 11-tetraazabicyclo [6.6. 2] hexadecane (CB-TE2A) derivatives.[9–11] For these BFCs, relatively harsh conditions such as elevated temperature were generally required for 64Cu chelation. Recently, a new class of BFCs has been