Mn(II)-monosubstituted polyoxometalates as candidates for contrast agents in magnetic resonance imaging

Two mono-substituted manganese polyoxometalates, K6MnSiW11O39 (MnSiW11) and K8MnP2W17O61 (MnP2W17), have been evaluated by in vivo and in vitro experiments as the candidates of potential tissue-specific contrast agents for magnetic resonance imaging (MRI). T-1-relaxivities of 12.1 mM(-1) s(-1) for MnSiW11 and 4.7 mM(-1) s(-1) for MnP2W17 (400 MHz, 25 degrees C) were higher than or similar to that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in BSA and hTf solutions were also reported. After administration of MnSiW11 and MnP2W17 to Wistar rats, MR imaging showed longer and remarkable enhancement in rat liver and favorable renal excretion capability. The signal intensity increased by 74.0 +/- 4.9% for the liver during the whole imaging period (90 min) and by 67.2 +/- 5.3% for kidney within 20-70 min after injection at 40 +/- 3 mu mol kg(-1) dose for MnSiW11. MnP2W17 induced 71.5 +/- 15.1%. enhancement for the liver in 10-45 min range and 73.1 +/- 3.2% enhancement for kidney within 5-40 min after injection at 39 +/- 3 mu mol kg(-1) dose. In vitro and in vivo study showed MnSiW11 and MnP2W17 being favorable candidates as the tissue-specific contrast agents for MRI.

Arabinogalactan as a carrier for contrast agent in magnetic resonance imaging

Arabinogalactan-Gd-DTPA was synthesized by the reaction of diethylenetriaminepenta-acetic acid (DTPA) bisanhydride with polysaccharide in dry DMSO and characterized by FTIR, elemental analysis and ICP-AES. Its stability was investigated by competition with Ca2+, EDTA, DTPA. The t(1)-relaxivity is 8.06 mmol(-1) . L . s(-1) in D2O, 8.48 mmol(-1) . L . s(-1) in 0.725 mmol . L-1 BSA, respectively. t(1)-weighted MR imaging of rat kidney and liver showed a remarkable enhancement post injection of Arabinogalactan-Gd-DTPA. The results indicate that the arabinogalactan-Gd-DTPA is a potential contrast agent for MRI.

The gadolinium complexes with polyoxometalates as potential MRI contrast agents

The two gadolinium (Gd) polyoxometalates, K-15[Gd(BW11O39)(2)] [Gd(BW11)(2)] and K-17[Gd(CuW11O39)(2)] [Gd(CuW11)(2)] have been evaluated by in vivo and in vitro experiments as the candidates of potential tissue-specific magnetic resonance imaging (MRI) contrast agents. T-1 relaxivities of 17.12 mM(-1) . s(-1) for Gd(BW11)(2) and 19.95 mM(-1) . s(-1) for Gd(CuW11)(2) (400MHz, 25 degrees C) were much higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin solutions were also reported. After administration of Gd(BW11)(2) and Gd(CuW11)(2) to Wistar rats, MRI showed longer and remarkable enhancement in rat liver and favorable renal excretion capability. The signal intensity increased by 37.63 +/- 3.45% for the liver during the whole imaging period (100 min) and by 61.47 +/- 10.03% for kidney within 5-40 min after injection at 40 +/- 1-mu mol . kg(-1) dose for Gd(CuW11)(2), and Gd(BW11)(2) induced 50.44 +/- 3.51% enhancement in the liver in 5-50-min range and 61.47 +/- 10.03% enhancement for kidney within 5-40 min after injection at 39 +/- 4 mu mol . kg(-1) dose. In vitro and in vivo study showed that Gd(BW11)(2) and Gd(CuW11)(2) are favorable candidates as tissue-specific contrast agents for MRI.

Investigation of sandwiched gadolinium(III) complexes with tungstosilicates as potential MRI contrast agents

Two gadolinium-sandwiched complexes with tungstosilicates, K-13[Gd(SiW11O39)(2)] (Gd(SiW11)(2)) and K11H6[Gd2O3(SiW9O34)(2)] (Gd-3(SiW9)(2)), have been investigated by in vitro and in vivo experiments as potential contrast agents for magnetic resonance imaging (MRI). T-1-relaxivity of Gd(SiW11)(2)was 6.59 mM(-1) . s(-1) in aqueous solution and 6.85 mM(-1) . s(-1) in 0.725 mmol . L-1 bovine serum albumin solution at 25degreesC and 9.39 T, respectively. The corresponding T-1-relaxivity of Gd-3(SiW9)(2) was 12.6 and 19.3 mM(-1) . s(-1) per Gd, respectively. MRI for Sprague-Dawley rats showed longer and more remarkable enhancement in rat liver after i.v. injection of these two complexes: 39.4 +/- 3.9% and 57.4 +/- 11.6% within the first 30 min after injection, 31.2 +/- 2.6% and 39.9 +/- 7.6% in the next 60 min for Gd(SiW11)(2) and Gd-3(SiW9)(2) at doses of 0.081 and 0.084 mmol Gd/kg, respectively. Our preliminary in vitro and in vivo study indicates that Gd(SiW11)(2) and Gd-3(SiW9)(2) are favorable candidates for hepatic contrast agents for MRI. However, the two complexes exhibit higher acute toxicity and need to be modified and studied further before clinical use.

Gadolinium heteropoly complex K-17[Gd(P2W17O61)(2)] as a potential MRI contrast agent

Gadolinium heteropoly complex K-17[Gd(P2W17O61)(2)] has been evaluated by in vitro and in vivo experiments as a potential contrast agent for magnetic resonance imaging (MRI). The thermal analysis and conductivity study indicate that this complex has good thermal stability and wide pH stability range. The T-1 relaxivity is 7.59 mM(-1) s(-1) in aqueous solution and 7.97 mM(-1) s(-1) in 0.725 mmol l(-1) bovine serum albumin (BSA) solution at 25degreesC and 9.39 T, respectively. MR imaging of three male Sprague-Dawley rats showed remarkable enhancement in rat liver after intravenous injection, which persisted longer than with Gd-DTPA. The signal intensity increased by 57.1 +/- 16.9% during the whole imaging period at 0.082 mmol kg(-1) dose. Our preliminary in vitro and in vivo studies indicate that K-17[Gd(P2W17O61)(2)] is a potential liver-specific MRI contrast agent.

Comparison between GdDTPA and two gadolinium polyoxometalates as potential MRI contrast agents

Two gadolinium polyoxometalates, Gd2P2W18O62 and K-15[(GdO)(3)(PW9O34)(2)], have been evaluated by in vivo as well as in vitro experiments as the candidates of tissue-specific magnetic resonance imaging (MRI) contrast agents. T-1-relaxivities of 28.4 mM(-1)-s(-1) for Gd2P2W18O62 and 11.2 mM(-1)-s(-1) for K-15[(GdO)(3)(PW9O34)(2)] (400 MHz, 25 degreesC) were higher than that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in bovine serum albumin and human serum transferrin were also reported. The favorable liver-specific contrast enhancement and renal excretion capability in in vivo MRI with Sprague-Dawley rats after i.v. administration of K-15[(GdO)(3)(PW9O34)(2)] was demonstrated. In vivo and in vitro assay showed that K-15[(GdO)(3)(PW9O34)(2)] is a promising liver-specific MRI contrast agent. However, Gd2P2W18O62 did not show the favorable quality in vivo as expected from its high relaxivity in vitro, which was attributed to low bioavailability, indicating that it is of limited value as tissue-specific MRI contrast agent.

稀土化合物的一种新用途(上)——核磁共振成像(MRI)用造影剂

磁共振成像(Magnetic Resonance Imaging简称MRI)是近十几年来发展起来的一种新的医疗诊断手段,与x-射线计算机断层扫描(Computed Tomography简称x-CT)相比,具有明显的优点,如对脑部、腹腔部、椎间盘组织等的病变有较高的灵敏度。同时,由于磁场和射频电波对人体健康的损害远远小于x-CT产生的x-射线,因此,MRI法已成为当前

新型靶向性磁共振成像造影剂的合成及性质研究

磁共振成像(magnetic resonance imaging, MRI)以其分辨率高、对人体无电离辐射损伤、多参数成像等优点而得到迅速发展和广泛应用。目前，MRI已从单一形态学向分子影像学的深度发展，对医学临床和医学研究产生了巨大影响。为了提高病变部位与正常组织间信号的对比度，约30%~40%的诊断需要使用磁共振成像造影剂。它是一类能缩短成像时间、提高成像对比度和清晰度、显示组织器官功能状态的诊断用药。下一代磁共振成像造影剂的设计目标将集中在对特定组织或器官具有选择性或靶向性、高弛豫性能和减少用药剂量等方面。本论文在此领域的研究内容可归纳如下： (1) 以多糖为载体的MRI造影剂 设计合成了阿拉伯半乳聚糖修饰的Gd-DTPA配合物(Gd-DTPA-CMAG-An)和葡聚糖修饰的Gd-DTPA配合物(Gd-DTPA-CMDn-Cyst)。通过体外弛豫时间测试和体内磁共振成像实验研究了Gd-DTPA-CMAG-An弛豫性能、器官选择性、体内滞留时间和代谢情况，结合体外稳定性综合评价了其应用于临床的可能性。研究结果表明，Gd-DTPA-CMAG-An配合物在水溶液中弛豫性能为Gd-DTPA的1.4倍左右，Gd-DTPA-CMAG-A2对肝脏信号的增强效果是Gd-DTPA的2.0倍左右，并且能在较长时间内产生良好稳定的增强效果。这与肝脏表面的去唾液酸糖蛋白受体的专一性识别有关。Gd-DTPA-CMAG-A2良好的肝脏选择性和肾脏代谢能力，有望成为有前景的肝脏选择性造影剂。通过小鼠MRI实验初步评价了Gd-DTPA-CMDn-Cyst配合物造影剂对血管信号的增强作用。Gd-DTPA-CMD4-Cyst对血管产生了良好的增强效果，并且能在较长时间内对血管产生良好稳定的增强，从而有充分的时间优化成像窗口获得理想的成像效果。但造影剂在体内的分布和代谢是一个非常复杂的过程，Gd-DTPA-CMD4-Cyst在血液中的滞留情况及能否用于血管造影仍需进一步的实验证实。 (2) MnNaY 型分子筛作为胃肠道MRI造影剂 离子交换法制备了Mn2+交换的NaY分子筛MnNaY，从对造影剂的一般要求出发，对其酸性水溶液中的稳定性和离子交换选择性、体外弛豫性能和体内成像等方面进行研究，并对器官的选择性及体内滞留时间和代谢情况进行了分析，从而对其应用于临床的可能性进行了探讨。研究结果表明，MnNaY悬浮液能长时间在较低的酸性条件下保持良好的稳定性，其弛豫效率高于目前临床所用造影剂Gd-DTPA，随Mn2+的含量在NaY分子筛中的增加(3.2%~5.2%)，弛豫效率反而降低。MnNaY (3.2% Mn)对胃部具有良好的增强效果，并且能在较长时间内产生良好稳定的增强效果，有利于获得理想的成像效果。它是一种比较好的潜在口服胃肠道造影剂。 (3) 甘草酸为载体的MRI造影剂 合成了甘草酸为载体的配合物GL-(A-Gd-DTPA)3，对其体外弛豫性能和体内成像等方面进行了研究，结果表明，其在水中的弛豫效率约为目前临床所用造影剂Gd-DTPA的1.4倍，体内成像表明它能在较长时间内对大鼠肝脏产生良好稳定的增强效果，这是由于肝(实质)细胞膜表面存在GL和GA受体，Gd-DTPA 以GL为载体后具有良好的趋肝性与肝细胞靶向性。 (4) 中性的Gd-DTPA双酰胺衍生物 合成了两种中性的Gd-DTPA双酰胺衍生物Gd-DTPA-BBA和Gd-DTPA-BtBA，其弛豫效率与Gd-DTPA相近，对肝脏和肾脏具有较好的增强效果，由于这两种配合物均为电中性化合物，这样配合物溶液的渗透压值与血液的渗透压值较接近，可能更易为生物体所接受。

NMR studies of Gd(DTPA-BIN) in human serum albumin solution

Stable gadolinium complexes, such as Gd(DTPA) and Gd(DOTA), are usually used as the contrast agents for magnetic resonance imaging(MRI). Reported here are the enhanced relaxation properties of a novel gadolinium complex, diethylene-triaminopentaacetate Lis (isoniazid) [Gd(DTPA-BIN)], in aqueous and in human serum albumin(HSA) solution, which indicates that (1) two Gd(DTPA-BIN) can integrate non-covalently with one HSA with an equilibrium constant of 0. 02 mmol(-2) . L-2 ; (2) the relaxivities are 3. 28 and 4. 92 mmol(-1) . L . s(-1) for the free Gd(DTPA-BIN) and the [Gd(DTPA-BIN)](2), HSA conjugator, respectively; (3) the rotational correlation time of protein conjugator is notably higher than that of the free complex, The above results may imply that Gd(DTPA-BIN) has a higher tissue selectivity than that of its parent Gd(DTPA).

An evaluation of gadolinium polyoxornetalates as possible MRI contrast agent

Two gadolinium polyoxometalates, K9GdW10O36 and K-11 [Gd(PW11O39)(2)], have been evaluated both in vivo and in vitro as candidates for tissue-specific MRI contrast agents. T-1-relaxivities of 6.89 mM(-1) . s(-1) for K9GdW10O36 and 5.27 mM(-1) . s(-1) for K-11[Gd(PW11O39)(2)] are slightly higher than that of the commercial MRI contrast agent (Gd-DTPA). Both compounds bind with bovine serum albumin and human serum transferrin and favorable liver-specific contrast enhancement in in vivo MRI with Sprague-Dawley rats after i.v. administration has been demonstrated. Imaging studies demonstrate that the two agents have a long residence time, showing MR signal enhancement in the liver for more than 40 min, longer than commercially available contrast agents. In vivo and in vitro assays showed that GdW10 and Gd(PW11)(2) are promising liver-specific MRI contrast agents and GdW10 may be used in the diagnosis of the pathological state. However, with the higher acute toxicity, the two gadolinium polyoxometalates need to be modified and studied further before clinical use.