Positron Emission Tomography-Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A.
Positron Emission Tomography-Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A.
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DOI：
10.1097/rli.0000000000000736
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发表时间：
2021-04-01
影响因子：
6.7
通讯作者：
Gale EM
中科院分区：
文献类型：
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作者：
Zhou IY;Ramsay IA;Ay I;Pantazopoulos P;Rotile NJ;Wong A;Caravan P;Gale EM
Mn-PyC 3A是一种实验性锰（Mn）基细胞外液MRI造影剂，正在评估其作为临床钆基造影剂的直接替代品。本研究的目的是使用同步PET-MR成像来比较Mn-PyC 3A与肝脏特异性造影剂Mn-DPDP的全身药代动力学、生物分布和消除，确定Mn-PyC 3A在大鼠肾损伤模型中的药代动力学和排泄分数，并比较Mn-PyC 3A与钆特酸盐（Gd-DOTA）在大鼠肾损伤模型中的全身消除。Mn-PyC 3A和Mn-DPDP用正电子发射同位素Mn-52通过与52 MnCl 2的Mn 2+交换进行放射性标记。动态同步PET-MRI用于测量Mn-52的全身药代动力学和生物分布，在静脉内0.2mmol/kg剂量的[52 Mn] Mn-PyC 3A给正常或5/6肾切除大鼠或0.01mmol/kg剂量的[52 Mn]Mn-DPDP给正常大鼠后立即和7天。分别通过γ计数或Gd元素分析定量注射2.0 mmol/kg [52 Mn] Mn-PyC 3A（每个时间点n=11）或Gd-DOTA（每个时间点n=8）后大鼠的排泄分数、1天和7天的生物分布。采用非配对t检验比较正常和5/6肾切除大鼠中Mn-PyC 3A的药代动力学和体内生物分布，以及5/6肾切除大鼠中离体Mn与Gd生物分布数据的比较。动态PET-MR成像数据表明，[52 Mn] Mn-PyC 3A和[52 Mn]Mn-DPDP均通过肾脏和肝胆的混合消除消除，但更大部分的[52 Mn] Mn-PyC 3A通过肾脏滤过消除。全身PET图像显示，[52 Mn] Mn-PyC 3A中的Mn-52被有效地从体内消除，而[52 Mn]Mn-DPDP中的Mn-52则保留在全身。[52 Mn] Mn-PyC 3A在正常和5/6肾切除大鼠中的血液消除半衰期分别为13 ± 3.5 min和23 ± 12 min，P = 0.083。正常和5/6肾切除大鼠膀胱中注射后0 - 60 min的曲线下面积（AUC 0 -60）分别为2600 ± 1700% ID/cc*min和750 ± 180% ID/cc*min，P = 0.024，而正常和5/6肾切除大鼠肝脏中的AUC 0 -60分别为33 ± 13和71 ± 16，P = 0.011，表明5/6肾切除大鼠的肝胆消除增加。注射后1天，从5/6肾切除大鼠中回收的[52 Mn] Mn-PyC 3A中的Mn和Gd-DOTA中的Gd的%ID分别为2.0 ± 1.1和1.3 ± 0.34，P = 0.10，注射后7天分别为0.14 ± 0.11和0.41 ± 0.24，P = 0.0041。Mn-PyC 3A在正常大鼠体内的药代动力学与Mn-DPDP不同，其消除效率高于Mn-DPDP。Mn-PyC 3A从正常和5/6肾切除大鼠中有效消除，5/6肾切除大鼠的肝胆排泄分数增加。Mn-PyC 3A在7天后从5/6肾切除大鼠中比Gd-DOTA更完全地消除。
Mn-PyC3A is an experimental manganese- (Mn) based extracellular fluid MRI contrast agent that is being evaluated as a direct replacement for clinical gadolinium based contrast agents. The goals of this study were to use simultaneous PET-MR imaging to compare the whole body pharmacokinetics, biodistribution, and elimination of Mn-PyC3A with the liver specific contrast agent Mn-DPDP, determine the pharmacokinetics and fractional excretion of Mn-PyC3A in a rat model of renal impairment, and to compare whole body elimination of Mn-PyC3A to gadoterate (Gd-DOTA) in a rat model of renal impairment. Mn-PyC3A and Mn-DPDP were radiolabeled with the positron emitting isotope Mn-52 via Mn2+ exchange with 52MnCl2. Dynamic simultaneous PET-MRI was used to measure whole body pharmacokinetics and biodistribution of Mn-52 immediately and out to 7 days following an intravenous 0.2 mmol/kg dose of [52Mn]Mn-PyC3A to normal or to 5/6 nephrectomy rats or a 0.01 mmol/kg dose of [52Mn]Mn-DPDP to normal rats. The fractional excretion, 1 day and 7 day biodistribution in rats after injection of 2.0 mmol/kg [52Mn]Mn-PyC3A (n=11 per time point) or Gd-DOTA (n=8 per time point) were quantified by gamma counting or Gd elemental analysis, respectively. Comparisons of Mn-PyC3A pharmacokinetics and in vivo biodistribution in normal and 5/6 nephrectomy rats and comparisons of ex vivo Mn vs. Gd biodistribution data in 5/6 nephrectomy were made with an unpaired t-test. Dynamic PET-MR imaging data demonstrate that both [52Mn]Mn-PyC3A and [52Mn]Mn-DPDP are eliminated by mixed renal and hepatobiliary elimination, but that a greater fraction of [52Mn]Mn-PyC3A is eliminated by renal filtration. Whole body PET images show that Mn-52 from [52Mn]Mn-PyC3A is efficiently eliminated from the body while Mn-52 from [52Mn]Mn-DPDP is retained throughout the body. The blood elimination half-life of [52Mn]Mn-PyC3A in normal and 5/6 nephrectomy rats is 13 ± 3.5 min and 23 ± 12 min, respectively, P = 0.083. Area under the curve between 0 and 60 min post-injection (AUC0–60) in the bladder of normal and 5/6 nephrectomy rats are 2600 ± 1700 %ID/cc*min and 750 ± 180 %ID/cc*min, respectively, P = 0.024, while AUC0–60 in the liver of normal and 5/6 nephrectomy rats are 33 ± 13 and 71 ± 16, respectively, P = 0.011, indicating increased hepatobiliary elimination in 5/6 nephrectomy rats. The %ID of Mn from [52Mn]Mn-PyC3A and Gd from Gd-DOTA recovered from 5/6 nephrectomy rats 1 day after injection were 2.0 ± 1.1 and 1.3 ± 0.34, respectively, P = 0.10, and 7 days after injection were 0.14 ± 0.11 and 0.41 ± 0.24, respectively, P = 0.0041. Mn-PyC3A has different pharmacokinetics and is more efficiently eliminated than Mn-DPDP in normal rats. Mn-PyC3A is efficiently eliminated from both normal and 5/6 nephrectomy rats, with increased fractional hepatobiliary excretion from 5/6 nephrectomy rats. Mn-PyC3A is more completely eliminated than Gd-DOTA from 5/6 nephrectomy rats after 7 days.