Tetraamine-Derived Bifunctional Chelators for Technetium-99m Labelling: Synthesis, Bioconjugation and Evaluation as Targeted SPECT Imaging Probes for GRP-Receptor-Positive Tumours
Tetraamine-Derived Bifunctional Chelators for Technetium-99m Labelling: Synthesis, Bioconjugation and Evaluation as Targeted SPECT Imaging Probes for GRP-Receptor-Positive Tumours
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DOI：
10.1002/chem.200902011
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发表时间：
2010-01-01
影响因子：
4.3
通讯作者：
Maecke, Helmut R.
中科院分区：
文献类型：
--
作者：
Abiraj, Keelara;Mansi, Rosalba;Maecke, Helmut R.
由于其最佳的核特性、易于获得、低成本和有利的剂量测定，(99m)Tc 仍然是医学成像应用的理想放射性同位素。基于四胺骨架的双功能螯合剂易于与 Tc(V)O(2) 络合，形成具有高体内稳定性和显着亲水性的单阳离子物质，从而具有良好的药代动力学。本文描述了一系列 1,4,8,11-四氮杂十一烷衍生物 (01-06) 的合成，这些衍生物在 6 位上含有不同的官能团，用于生物分子的缀合以及随后用 (99m) Tc 进行标记。螯合剂01用作起始材料，用于轻松合成用OH(02)、N3(04)和O-琥珀酯(05)基团官能化的螯合剂。通过使用廉价且可商购的起始材料，实现了羧基官能化四胺基螯合剂06的直接且容易的合成。将 06 与有效的铃蟾肽拮抗剂肽缀合，然后用 (99m)Tc 标记，得到放射性示踪剂 (99m)Tc-N4-BB-ANT，放射性标记产率 >97%，比活度为 37 GBq mu mol(-1)。获得的IC(50)值为(3.7+/-1.3)nm，这证实了缀合物与胃泌素释放肽受体(GRPr)的高亲和力。免疫荧光和钙动员测定证实了缀合物的强拮抗特性。 (99m)Tc-N4-BB-ANT 的体内药代动力学研究表明，在 PC3 异种移植物和其他 GRPr 阳性器官中具有高特异性摄取。注射后 1 小时 (p.i.) 时，肿瘤摄取为 (22.5 +/- 2.6)% 注射活性每克 (%IAg(-1))。注射后 4 小时增加至 (29.9 +/- 4.0)%IAg(-1) SPECT/计算机断层扫描 (CT) 图像显示腹部肿瘤摄取量高、背景清晰且放射性可忽略不计。 (99m)Tc-N4-BB-ANT 令人鼓舞的临床前结果保证了其潜在的临床转化候选资格。
Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, (99m)Tc continues to be the ideal radioisotope for medical-imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O(2) to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11-tetra-azaundecane derivatives (01-06) containing different functional groups at the 6-position for the conjugation of biomolecules and subsequent labelling with (99m)Tc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH (02), N3 (04) and O-succinyl ester (05) groups. A straightforward and easy synthesis of carboxyl-functionalised tetraamine-based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin-antagonist peptide and subsequent labelling with (99m)Tc afforded the radiotracer (99m)Tc-N4-BB-ANT, with radiolabelling yields of >97% at a specific activity of 37 GBq mu mol(-1). An IC(50) value of (3.7 +/- 1.3) nm was obtained, which confirmed the high affinity of the conjugate to the gastrin-releasing-peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of (99m)Tc-N4-BB-ANT showed high and specific uptake in PC3 xenografts and in other GRPr-positive organs. ne tumour uptake was (22.5 +/- 2.6)% injected activity per gram (%IAg(-1)) at I h post injection (p.i.). and increased to (29.9 +/- 4.0)%IAg(-1) at 4h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of (99m)Tc-N4-BB-ANT warrant its potential candidature for clinical translation.