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Maternal and Fetal ¹¹C-Cocaine Uptake and Kinetics Measured In Vivo by Combined PET and MRI in Pregnant Nonhuman Primates

¹ Medical Department, Brookhaven National Laboratory, Upton, New York
² Department of Anesthesiology, State University of New York at Stony Brook, Stony Brook, New York
³ Chemistry Department, Brookhaven National Laboratory, Upton, New York
⁴ Department of Psychiatry, State University of New York Downstate, Brooklyn, New York
⁵ National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

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 ¹¹C-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 ¹¹C-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 ¹¹C-cocaine were calculated. Results: Coregistration of PET and MR images allowed identification of fetal organs and brain regions and demonstrated that ¹¹C-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 ¹¹C 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. Conclusion: 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 ¹¹C-cocaine is lower and slower than in the maternal brain, a measurable quantity of ¹¹C-cocaine (or its labeled metabolites) accumulates in the fetal brain at early times after injection. The highest accumulation of ¹¹C 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.

Key Words: ¹¹C-cocaine • maternal-fetal exchange • PET • MRI • primate

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