Laboratoire de Génomique, Bioinformatique et Chimie Moléculaire (EA 7528), Equipe Chimie Moléculaire, Conservatoire National des Arts et Métiers (CNAM), HESAM Université, Paris, France.
Invest Radiol. 2019 Aug;54(8):475-484. doi: 10.1097/RLI.0000000000000563.
We aimed to evaluate gadopiclenol, a newly developed extracellular nonspecific macrocyclic gadolinium-based contrast agent (GBCA) having high relaxivity properties, which was designed to increase lesion detection and characterization by magnetic resonance imaging.
We described the molecular structure of gadopiclenol and measured the r1 and r2 relaxivity properties at fields of 0.47 and 1.41 T in water and human serum. Nuclear magnetic relaxation dispersion profile measurements were performed from 0.24 mT to 7 T. Protonation and complexation constants were determined using pH-metric measurements, and we investigated the acid-assisted dissociation of gadopiclenol, gadodiamide, gadobutrol, and gadoterate at 37°C and pH 1.2. Applying the relaxometry technique (37°C, 0.47 T), we investigated the risk of dechelation of gadopiclenol, gadoterate, and gadodiamide in the presence of ZnCl2 (2.5 mM) and a phosphate buffer (335 mM). Pharmacokinetics studies of radiolabeled Gd-gadopiclenol were performed in Beagle dogs, and protein binding was measured in rats, dogs, and humans plasma and red blood cells.
Gadopiclenol [gadolinium chelate of 2,2',2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid); registry number 933983-75-6] is based on a pyclen macrocyclic structure. Gadopiclenol exhibited a very high relaxivity in water (r1 = 12.2 mM·s at 1.41 T), and the r1 value in human serum at 37°C did not markedly change with increasing field (r1 = 12.8 mM·s at 1.41 T and 11.6 mM·s at 3 T). The relaxivity data in human serum did not indicate protein binding. The nuclear magnetic relaxation dispersion profile of gadopiclenol exhibited a high and stable relaxivity in a strong magnetic field. Gadopiclenol showed high kinetic inertness under acidic conditions, with a dissociation half-life of 20 ± 3 days compared with 4 ± 0.5 days for gadoterate, 18 hours for gadobutrol, and less than 5 seconds for gadodiamide and gadopentetate. The pharmacokinetic profile in dogs was typical of extracellular nonspecific GBCAs, showing distribution in the extracellular compartment and no metabolism. No protein binding was found in rats, dogs, and humans.
Gadopiclenol is a new extracellular and macrocyclic Gd chelate that exhibited high relaxivity, no protein binding, and high kinetic inertness. Its pharmacokinetic profile in dogs was similar to that of other extracellular nonspecific GBCAs.
我们旨在评估一种新型的细胞外非特异性大环钆基造影剂（GBCA）gadopiclenol，它具有高弛豫性能，旨在通过磁共振成像提高病变的检测和特征描述。
我们描述了 gadopiclenol 的分子结构，并在 0.47 和 1.41 T 场中测量了水和人血清中的 r1 和 r2 弛豫率特性。进行了从 0.24 mT 到 7 T 的核磁共振弛豫分散谱测量。使用 pH 测量法确定了质子化和络合常数，并研究了 37°C 和 pH 1.2 下 gadopiclenol、gadodiamide、gadobutrol 和 gadoterate 的酸辅助解离。应用弛豫率技术（37°C，0.47 T），我们研究了 gadopiclenol、gadoterate 和 gadodiamide 在存在 2.5 mM ZnCl2 和 335 mM 磷酸盐缓冲液时的去螯合风险。在比格犬中进行了放射性标记的 Gd-gadopiclenol 的药代动力学研究，并在大鼠、狗和人血浆和红细胞中测量了蛋白结合。
gadopiclenol [2,2',2″-(3,6,9-三氮杂-1(2,6)-吡啶环十二烷-3,6,9-三基)三(5-((2,3-二羟基丙基)氨基)-5-氧戊酸)的钆螯合物；注册号 933983-75-6]基于 pyclen 大环结构。gadopiclenol 在水中表现出非常高的弛豫率（在 1.41 T 时 r1 = 12.2 mM·s），并且 37°C 时人血清中的 r1 值随场强的增加没有明显变化（在 1.41 T 时 r1 = 12.8 mM·s，在 3 T 时 r1 = 11.6 mM·s）。人血清中的弛豫率数据表明没有蛋白结合。gadopiclenol 的磁共振弛豫弥散谱在强磁场中表现出高且稳定的弛豫率。gadopiclenol 在酸性条件下表现出高的动力学惰性，其半衰期为 20 ± 3 天，而 gadoterate 为 4 ± 0.5 天，gadobutrol 为 18 小时，gadodiamide 和 gadopentetate 则小于 5 秒。在犬中的药代动力学特征与其他细胞外非特异性 GBCA 相似，表现为分布在细胞外间隙，无代谢。在大鼠、狗和人中均未发现蛋白结合。
gadopiclenol 是一种新型的细胞外大环 Gd 螯合物，具有高弛豫率、无蛋白结合和高动力学惰性。在犬中的药代动力学特征与其他细胞外非特异性 GBCA 相似。
