Benveniste Helene, Fowler Joanna S, Rooney William D, Moller Daryn H, Backus W Walter, Warner Donald A, Carter Pauline, King Payton, Scharf Bruce, Alexoff David A, Ma Yeming, Vaska Paul, Schlyer David, Volkow Nora D
Medical Department, Brookhaven National Laboratory, Upton, New York 11793, USA.
J Nucl Med. 2003 Sep;44(9):1522-30.
An understanding of how drugs are transferred between mother and fetus during the gestational period is an important medical issue of relevance to both therapeutic drugs and drugs of abuse. Though there are several in vitro and in vivo methods to examine this issue, all have limitations. Furthermore, ethical and safety considerations generally preclude such studies in pregnant humans. PET and appropriately labeled compounds have the ability to provide information on both maternal-fetal drug pharmacokinetics and pharmacodynamics. We present here a nonhuman primate animal model and the methodology for combining PET and MRI to identify fetal organs and to measure maternal and fetal isotope distribution using (18)F-FDG and a whole-body imaging protocol to demonstrate proof-of-principle.
One nonpregnant nonhuman primate was used for determination of the anesthesia protocol and MRI methods and 3 pregnant nonhuman primates (Macaques radiata) weighing 4.5-7 kg were used for the imaging study and anesthetized with propofol (160-300 micro g/kg/min). Anatomic T2-weighted MR images were acquired on a 4-T MR instrument. Subsequently, whole-body PET images were acquired 35 min after injection of (18)F-FDG, and standardized uptake values (SUVs) were calculated. Image processing and coregistration were performed using commercial software.
All animals underwent uneventful general anesthesia for a period of up to 7 h. Coregistration of PET and MR images allowed identification of fetal organs and demonstrated that (18)F-FDG readily crosses the placenta and that (18)F accumulates in both maternal and fetal brain, heart, and bladder. Brain SUVs averaged 1.95 +/- 0.08 (mean +/- SD) and 1.58 +/- 0.11 for mothers and fetuses, respectively. Monkeys delivered healthy babies after a normal gestational term of 170 d following the PET/MRI study.
The pregnant macaque in combination with PET and MRI technology allows the measurement of radioisotope distribution in maternal and fetal organs. This demonstrates the potential for noninvasively measuring the transfer of drugs across the placenta and for measuring the fetal drug distribution. It also opens up the possibility for studying binding and elimination as well as the effects of a drug on specific cellular elements and physiologic processes during the gestational period in a primate model.
了解妊娠期药物在母体和胎儿之间的转移方式是一个与治疗药物和滥用药物都相关的重要医学问题。尽管有多种体外和体内方法来研究这个问题，但都存在局限性。此外，伦理和安全方面的考虑通常使此类研究无法在孕妇身上进行。正电子发射断层扫描（PET）和适当标记的化合物能够提供有关母胎药物药代动力学和药效学的信息。我们在此展示一种非人灵长类动物模型以及将PET和磁共振成像（MRI）相结合的方法，以识别胎儿器官，并使用（18）F - 氟代脱氧葡萄糖（FDG）和全身成像方案来测量母体和胎儿的同位素分布，从而证明原理。
使用1只未怀孕的非人灵长类动物来确定麻醉方案和MRI方法，3只体重4.5 - 7千克的怀孕非人灵长类动物（辐射猕猴）用于成像研究，并用丙泊酚（160 - 300微克/千克/分钟）麻醉。在一台4 - T MR仪器上采集解剖学T2加权MR图像。随后，在注射（18）F - FDG后35分钟采集全身PET图像，并计算标准化摄取值（SUVs）。使用商业软件进行图像处理和配准。
所有动物均接受了长达7小时的平稳全身麻醉。PET和MR图像的配准使得能够识别胎儿器官，并表明（18）F - FDG很容易穿过胎盘，且（18）F在母体和胎儿的脑、心脏及膀胱中均有积聚。母体和胎儿脑的SUVs平均值分别为1.95±0.08（均值±标准差）和1.58±0.11。在PET/MRI研究后的170天正常妊娠期后，猴子产下了健康的幼崽。
怀孕猕猴与PET和MRI技术相结合，能够测量母体和胎儿器官中的放射性同位素分布。这证明了无创测量药物跨胎盘转移以及测量胎儿药物分布的潜力。它还为在灵长类动物模型中研究药物结合与消除以及药物在妊娠期对特定细胞成分和生理过程的影响开辟了可能性。
