Pregnant primates aid PET project

Scientists in the US have demonstrated a new way to assess the potentially damaging effects of prenatal drug exposure using non-invasive medical-imaging tools. The technique could also be used to monitor a foetus’s response to therapeutic drugs.

Scientists at the US Department of Energy’s Brookhaven National Laboratory used magnetic resonance imaging (MRI) combined with positron emission tomography (PET) to track the uptake and distribution of trace amounts of cocaine in pregnant monkeys. They found significant differences in where and how fast the drug accumulates in maternal and foetal organs.

“Understanding how drugs are transferred between a mother and her foetus during pregnancy may help us unravel the mechanisms of the drug’s damaging effects on unborn children,” said Helene Benveniste, Chair of Brookhaven’s Medical Department. “While studies that follow human drug abusers and their children over decades provide valuable information, animal studies can more quickly provide clues to the underlying mechanisms of damage and suggest ways to test new treatment or prevention strategies,” she said.

The imaging tools could also be used to assess the effects of therapeutic drugs, for example, synthetic narcotics administered to pregnant women following surgical procedures performed on foetuses in utero.

“Following such surgeries, which are becoming more common to correct congenital malformations, the mother is treated with narcotics for pain and anaesthesiologists are relying on the mother transferring the pain medication to the foetus via the placenta. But we actually do not know if what we give is sufficient to ‘satisfy’ the pain level of the foetus,” said Benveniste, who is also a professor of anaesthesiology at Stony Brook University.

Though other scientists have attempted to use PET to non-invasively monitor maternal-foetal drug exchange and pharmacokinetics (how quickly a drug is taken up and distributed among the body’s organs), the PET technique alone did not provide adequate anatomical detail of the tiny foetal organs.

The current study combined PET with high-resolution magnetic resonance imaging (MRI) – complementary non-invasive techniques available at Brookhaven Lab’s Center for Translational Neuroimaging – to track cocaine pharmacokinetics down to the level of the placenta and individual regions of the foetal brain.

“The MRI images, which have the necessary detail, served as a high-resolution anatomical template onto which we ‘overlayed’ the PET pharmacokinetic data using sophisticated computer techniques,” Benveniste said. “The resulting images gave us the best of both worlds and allowed us to look at cocaine uptake and distribution in the mother and foetus simultaneously.”

The animals were anaesthetised prior to scanning. MRI scans were performed first, followed by PET. For the PET study, each animal was injected with a trace quantity of cocaine, less than 10 micrograms, which is not enough to cause pharmacological effects.

The injected cocaine had previously been “labelled,” or “tagged,” with a short-lived radioactive form of carbon (carbon-11). This “radiotracer” emits a signal that is picked up by the PET scanner, which takes “snapshots” of the tracer’s location over time to show how much and how quickly the cocaine (and/or the metabolic byproducts that retain the carbon-11) enters and clears the various organs. The radiotracer decays and completely clears from the animal’s body in about two hours. After the procedure, the animals were returned to their social colony to deliver their offspring.

The combined images show that cocaine and/or its labelled metabolites readily cross the placenta. But the cocaine uptake distribution pattern observed in the foetus was very different from that of the mother. For example, mothers showed rapid uptake and clearance of the drug in the heart, kidneys, and lungs, with slower uptake in the liver and brain. In the foetus, cocaine accumulated at the highest levels in the liver (due to the unique anatomy of foetal circulation) and to a lesser extent in the brain.

“While the uptake of the tracer into the foetal brain is lower and slower than in the mother’s brain, a measurable quantity of cocaine and/or its labelled metabolites does accumulate in the foetal brain, particularly in the striatum, where cocaine is known to bind to cell-surface receptors that result in a euphoric response,” Benveniste said.

The high uptake of radiolabelled cocaine in the placenta is also particularly relevant, the researchers said, because cocaine is known to constrict blood vessels in the placenta. It may be that this constriction of placental blood flow is one of the mechanisms underlying the harmful effects of cocaine exposure during pregnancy.