Maternal and fetal 11C-cocaine uptake and kinetics measured in vivo by combined PET and MRI in pregnant nonhuman primates.
Cocaine use during pregnancy has been shown to be deleterious to the infant. This may reflect reduction of flow to placenta or effects on the fetal brain. Methods to assess pharmacokinetics of drugs of abuse in vivo would be useful to investigate the mechanisms underlying the fetal adverse effects. We recently reported that combined MRI and PET technology allows the measurement of radioisotope distribution in maternal and fetal organs in pregnant Macaca radiata. Here, we evaluate the utility of PET to measure the uptake and distribution of (11)C-cocaine in the third-trimester fetus.


METHODS
Six pregnant M. radiata weighing 3.8-9.0 kg were anesthetized and MR images were acquired on a 4-T MRI instrument. In all 6 animals, dynamic PET scans were subsequently acquired using 148-259 MBq of (11)C-cocaine. Time-activity curves for both maternal and fetal organs were obtained simultaneously with the pregnant animal positioned transverse in the PET scanner. Distribution volume ratios for maternal and fetal brain for (11)C-cocaine were calculated.


RESULTS
Coregistration of PET and MR images allowed identification of fetal organs and brain regions and demonstrated that (11)C-cocaine or its labeled metabolites readily cross the placenta and accumulate mainly in fetal liver and to a lesser extent in the brain. Time to reach peak (11)C uptake in brain was shorter for the mother than for the fetus. The distribution volume ratios of the maternal striatum were higher than those of the fetus. Placenta was clearly visible on the early time frames and showed more rapid uptake and clearance than other fetal tissues.


CONCLUSIONS
The pregnant M. radiata model allows the noninvasive measurement of radioisotope pharmacokinetics in maternal and fetal brain and other organs simultaneously. Although the uptake of radioactivity into the fetal brain after the injection of (11)C-cocaine is lower and slower than in the maternal brain, a measurable quantity of (11)C-cocaine (or its labeled metabolites) accumulates in the fetal brain at early times after injection. The highest accumulation of (11)C occurs in the fetal liver. Rapid radioisotope accumulation and clearance in the placenta offer potential as an input function for kinetic modeling for future studies of binding site availability.
Benveniste
Helene
H
Medical Department, Brookhaven National Laboratory, Upton, New York 11793, USA. Benveniste@bnl.gov
Fowler
Joanna S
JS
Rooney
William
W
Ding
Yu-Shin
YS
Baumann
Angela L
AL
Moller
Daryn H
DH
Du
Congwu
C
Backus
Walter
W
Logan
Jean
J
Carter
Pauline
P
Coplan
Jeremy D
JD
Biegon
Anat
A
Rosenblum
Leonard
L
Scharf
Bruce
B
Gatley
John S
JS
Volkow
Nora D
ND
D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000196:embryology* / Q000378:metabolism; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D003042:Cocaine / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000000981:diagnostic imaging / Q000378:metabolism; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D007700:Kinetics; D008255:Macaca radiata; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008431:Maternal-Fetal Exchange / Q000502:physiology; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D011247:Pregnancy; D011270:Pregnancy, Animal; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013382:Subtraction Technique; D014018:Tissue Distribution
D002247:Carbon Isotopes; D019275:Radiopharmaceuticals; D003042:Cocaine