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首页> 外文期刊>Dalton transactions: An international journal of inorganic chemistry >Synthesis, conjugation and relaxation studies of gadolinium(iii)-4- benzothiazol-2-yl-phenylamine as a potential brain specific MR contrast agent
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Synthesis, conjugation and relaxation studies of gadolinium(iii)-4- benzothiazol-2-yl-phenylamine as a potential brain specific MR contrast agent

机译：iii（iii）-4-苯并噻唑-2-基-苯胺作为潜在的大脑特异性MR造影剂的合成，结合和弛豫研究

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Magnetic resonance (MR) imaging is widely used in clinical research to map the structural and functional organization of the brain. We have designed and synthesized a Gd-based specific MR contrast agent that binds to regions in the brain. The presented compound {4-[(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]- 7,10-bis-carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl} acetic acid (DO3A-BT) was synthesized by conjugating the chloroacetylated product of 4-benzothiazol-2-yl-phenylamine with a trisubstituted cyclen. The lanthanide complex (Ln-DO3A-BT) was evaluated in vitro for both MR (Gd-DO3A-BT) and optical (Eu-DO3A-BT) imaging applications. The complex Gd-DO3A-BT displays a relaxivity of r_1 = 4.18 mM~(-1) s~(-1) at 4.7 T which is 1.2 times greater than Dotarem and significantly higher than the brain specific MR contrast agent Luxol Fast Blue (LFB). The protonation constant of the ligand (pK_(a1) = 9.91, pK_(a2) = 8.22, pK_(a3) = 5.01) and the stability constant of the complex formed between Gd(iii), Eu(iii) and Ca(ii) and ligand DO3A-BT (log β_(GdL) = 18.4, log β_(EuL) = 18.3, log β_(Zn2L) = 7.1, log β_(Ca2L) = 6.3) were recorded by potentiometric titration. The constants reflect the high stability of the ligand with lanthanides compared with endogenous metal ions. The transmetalation stability of Gd-DO3A-BT toward Zn proved to be excellent with a rate constant of 3.07 × 10~(-5) s~(-1) which is in line with other tetraazatetraacetic acid (DOTA)-monoamide complexes. The hydration number (q) was found to be 0.92, and is calculated from the difference in the luminescence lifetime of Eu-DO3A-BT in H_2O and D_2O solutions to determine the coordination state of this complex. The in vivo biodistribution of ~(99m)Tc-DO3A-BT in BALB/c mice showed a brain uptake of 1.2% ID g~(-1) at 2 min post injection when injected with mannitol which disrupts the blood-brain-barrier (BBB) due to osmotic shock. In vitro binding on the brain homogenate revealed a high uptake by the neuronal/glial cells for in vivo applications.
机译：磁共振（MR）成像已广泛用于临床研究，以绘制大脑的结构和功能组织图。我们已经设计并合成了一种基于Gd的特异性MR造影剂，该造影剂与大脑区域结合。提出的化合物{4-[（（4-苯并噻唑-2-基-苯基氨基甲酰基）-甲基]-7,10-双-羧甲基-1,4,7,10-四氮杂环十二烷基-1-基}乙酸（DO3A-BT ）是通过将4-苯并噻唑-2-基-苯胺的氯乙酰化产物与三取代的环素结合而合成的。对于MR（Gd-DO3A-BT）和光学（Eu-DO3A-BT）成像应用，都对镧系元素络合物（Ln-DO3A-BT）进行了体外评估。复杂的Gd-DO3A-BT在4.7 T下的弛豫度为r_1 = 4.18 mM〜（-1）s〜（-1），比Dotarem大1.2倍，并且显着高于大脑特异性MR造影剂Luxol Fast Blue（ LFB）。配体的质子化常数（pK_（a1）= 9.91，pK_（a2）= 8.22，pK_（a3）= 5.01）和Gd（iii），Eu（iii）和Ca（ii）之间形成的配合物的稳定常数）和配体DO3A-BT（logβ_（GdL）= 18.4，logβ_（EuL）= 18.3，logβ_（Zn2L）= 7.1，logβ_（Ca2L）= 6.3）记录。该常数反映了与内源性金属离子相比，具有镧系元素的配体的高稳定性。 Gd-DO3A-BT对Zn的金属转移稳定性证明是极好的，其速率常数为3.07×10〜（-5）s〜（-1），与其他四氮杂四乙酸（DOTA）-单酰胺配合物一致。发现水合数（q）为0.92，并且根据Eu-DO3A-BT在H_2O和D_2O溶液中的发光寿命的差异来计算以确定该配合物的配位状态。 〜（99m）Tc-DO3A-BT在BALB / c小鼠中的体内生物分布显示，注射甘露醇后2分钟注射后2分钟的大脑摄取为1.2％ID g〜（-1），破坏了血脑屏障（BBB）由于渗透性休克。在脑匀浆上的体外结合显示了神经元/神经胶质细胞对体内应用的高摄取。

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