Positron Emission Tomography–Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A

体内分布 药代动力学 核医学 化学 体内 放射化学 正电子发射断层摄影术 肾脏生理学 医学 磁共振成像 药理学 肾功能 放射科 体外 生物化学 有机化学 生物技术 生物
作者
Iris Y. Zhou,Ian Ramsay,İlknur Ay,Pamela Pantazopoulos,Nicholas J. Rotile,Alison Wong,Peter Caravan,Eric M. Gale
出处
期刊:Investigative Radiology [Lippincott Williams & Wilkins]
卷期号:56 (4): 261-270 被引量:37
标识
DOI:10.1097/rli.0000000000000736
摘要

Objectives Mn-PyC3A is an experimental manganese (Mn)-based extracellular fluid magnetic resonance imaging (MRI) contrast agent that is being evaluated as a direct replacement for clinical gadolinium (Gd)-based contrast agents. The goals of this study were to use simultaneous positron emission tomography (PET)–MRI to (1) compare the whole-body pharmacokinetics, biodistribution, and elimination of Mn-PyC3A with the liver-specific contrast agent mangafodipir (Mn-DPDP), (2) determine the pharmacokinetics and fractional excretion of Mn-PyC3A in a rat model of renal impairment, and (3) compare whole-body elimination of Mn-PyC3A to gadoterate (Gd-DOTA) in a rat model of renal impairment. Methods Mn-PyC3A and Mn-DPDP were radiolabeled with the positron emitting isotope Mn-52 via Mn 2+ exchange with 52 MnCl 2 . Dynamic simultaneous PET-MRI was used to measure whole-body pharmacokinetics and biodistribution of Mn-52 immediately and out to 7 days after an intravenous 0.2 mmol/kg dose of [ 52 Mn]Mn-PyC3A to normal or to 5/6 nephrectomy rats or a 0.01 mmol/kg dose of [ 52 Mn]Mn-DPDP to normal rats. The fractional excretion and 1- and 7-day biodistribution in rats after the injection of 2.0 mmol/kg [ 52 Mn]Mn-PyC3A (n = 11 per time point) or 2.0 mmol/kg 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 versus Gd biodistribution data in 5/6 nephrectomy were made with an unpaired t test. Results Dynamic PET-MRI data demonstrate that both [ 52 Mn]Mn-PyC3A and [ 52 Mn]Mn-DPDP were eliminated by mixed renal and hepatobiliary elimination but that a greater fraction of [ 52 Mn]Mn-PyC3A was eliminated by renal filtration. Whole-body PET images show that Mn-52 from [ 52 Mn]Mn-PyC3A was efficiently eliminated from the body, whereas Mn-52 from [ 52 Mn]Mn-DPDP was retained throughout the body. The blood elimination half-life of [ 52 Mn]Mn-PyC3A in normal and 5/6 nephrectomy rats was 13 ± 3.5 minutes and 23 ± 12 minutes, respectively ( P = 0.083). Area under the curve between 0 and 60 minutes postinjection (AUC 0–60 ) in the bladder of normal and 5/6 nephrectomy rats was 2600 ± 1700 %ID/cc*min and 750 ± 180 %ID/cc*min, respectively ( P = 0.024), whereas AUC 0–60 in the liver of normal and 5/6 nephrectomy rats was 33 ± 13 %ID/cc*min and 71 ± 16 %ID/cc*min, respectively ( P = 0.011), indicating increased hepatobiliary elimination in 5/6 nephrectomy rats. The %IDs of Mn from [ 52 Mn]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). Conclusions 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.
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