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Radioactive Cocaine Analogue Sheds Light on Brain

"THE story behind the diagnostic drug that could someday lead to a cure for Parkinson's disease has all the elements of an international thriller: A Penn scientist flies to Asia without telling most of his colleagues. Once there, he injects himself with a radioactive cocaine-like substance based on a formula that he and his team of researchers have just developed. Then he puts his head in an imaging machine -- a SPECT scanner, as it's called -- and makes a picture of his brain.
   Competing researchers around the country gnash their teeth. The Federal Drug Administration, which has no jurisdiction over such activities in foreign countries, fires off some testy letters to the University, which in turn is less than amused -- especially after it is sued by a former radiation-safety officer who claims that he was axed for reporting that the scientist had skirted federal regulations and University policy. (Penn argues vigorously that the officer was fired for other reasons.)
   
But the Society of Nuclear Medicine hails that cerebral self-portrait as the "image of the year." The European Journal of Nuclear Medicine presents its annual award for Best Science Paper to the scientist who developed the image-enhancing drug. And the drug itself, known as TRODAT-1, appears to have the potential to play an extremely important role in the diagnosis of Parkinson's disease and other dopamine-related disorders -- and to offer insights into certain cerebral differences between men and women. It has also since been approved by the FDA.
   The scientist's name is Dr. Hank F. Kung, chief of radiopharmaceutical chemistry at Penn. TRODAT is a tropane, a close cousin of cocaine or cocaine analogue. Like cocaine, TRODAT follows the flow of dopamine -- a chemical messenger known as a neurotransmitter -- to the dopamine transporters in the basal ganglia, which one researcher defines as "strategic relay centers that help different parts of the brain coordinate the execution of complex cognitive and motoric functions."

The TRODAT-illuminated brain of a healthy 66-year-old man, left, shows a far higher concentration of dopamine transporters than does the brain of a 63-year-old man with Parkinson's disease, right.

   Since Parkinson's patients have a dramatic loss of dopamine transporters, finding a safe drug that can illuminate them is of profound importance for diagnosing the disease. TRODAT, which contains an atom of radioactive technetium-99m, can be imaged by a SPECT (Single Photon Emission Computational Tomography) scanner, which operates by emitting photons (the component of light). But unlike the tropanes being developed by other researchers, TRODAT is cheap, safe, and highly effective as an imaging agent.
   Dr. David Mozley, associate professor of radiology and psychiatry, has collaborated with Kung and has been using TRODAT to measure the concentration of dopamine transporters in Parkinson's patients and other people. While he doubts that TRODAT will ever prove to be a financial gold mine for the University, he acknowledges that there has been an "intense competition" to develop the drug and a "lot of prestige" in getting it patented.
   "Labeling a receptor compound with technetium has been a Holy Grail of radiochemists for a long time," he says. "It's a remarkably difficult feat to accomplish."
   
TRODAT has already attracted considerable interest from pharmaceutical companies, though it has not yet received a patent. According to Dr. Peter B. Kramer, director of licensing in physical sciences at Penn's Center for Technology Transfer, the CTT has licensed the patent rights to a company (whose identity he would not disclose) in exchange for option payments and other considerations.
   "I think TRODAT is a significant compound that will be useful in diagnosing Parkinson's disease," says Kramer. "Early results indicate that the drug passes through the blood-brain barrier, even though it's been labeled with technetium, and that's a difficult feat. Hank Kung has accomplished something quite remarkable."
   "Right now, it's more or less a chicken-and-egg situation," explains Kung. "It's very difficult for a drug company to develop a neurodegenerative detection agent, because they could not open up everybody's brain. Neurodegenerative disease is a very slow process, hard to evaluate. By making this readily available, it will provide a very useful tool for developing a drug that will fight neurodegenerative diseases such as Parkinson's."
   In addition to demonstrating TRODAT's diagnostic value for Parkinson's disease, Mozley's current research also indicates that men in general have slightly higher concentrations of dopamine transporters than women, and that women have different concentrations depending on the stage of their menstrual cycle. In fact, he says, the highest concentration of dopamine transporters he has seen was in a woman who was still lactating, shortly after the cessation of breast-feeding.
   "We know that this receptor is the one that seems to be the most sensitive to the effects of estrogen," he explains, and high concentrations of the transporters appear to affect not just cognitive and physical tasks but also mood. "We know that women who are breast-feeding think a little bit differently," he adds. "Anecdotal observation for millennia suggests that they're more difficult to perturb, harder to rattle, when they're breast-feeding. And we come up with all kinds of psychological mumbo-jumbo to explain that -- some of which is probably true, at least at some core level, but there also are some biological correlates of that which have not been really explored."
   Mozley points out that originally, the Penn group "never even imagined" using TRODAT to evaluate a drug that could cure Parkinson's, and notes that the funding for its development came from the National Institute on Drug Abuse. (TRODAT is likely to be a useful tool in studying certain drug addictions.) He also acknowledges that TRODAT's primary use for Parkinson's patients is as a diagnostic tool, not a cure in itself, and that some neurologists will say "it's not going to do a bloody thing for people."
   
But since in his opinion, shared by some other neuroscientists, early intervention "not only retards the development of symptoms but actually may slow the progression of the disease," TRODAT's early-diagnostic abilities could be of critical importance. Mozley also notes that a new Brazilian drug known as Sygen is now being tested by colleagues at Thomas Jefferson University Hospital in Philadelphia and has shown promising results thus far. He and his Penn colleagues are now conducting studies using TRODAT to determine whether Sygen really does produce beneficial changes in the brain.
   Some three years ago, in order to test TRODAT, Kung flew to Korea and tried it on himself and a colleague, former Penn researcher Dr. Hee-Joung Kim of the Asan Medical Center in South Korea. (The University notes that "no radioactive materials were transported by Dr. Kung to Korea.") While the notion of injecting a close relative of cocaine into one's bloodstream sounds rather adventuresome for a highly regarded scientist, neither Kung nor anyone else could come close to getting high from the 20 millicuries of TRODAT.
   "For a layman, it sounds very exciting," Kung acknowledges, "but the chemical amount is probably one millionth of what is required for a pharmaceutical effect."
   By acting as his own guinea pig in a foreign country, Kung avoided the FDA's restrictions on testing a drug on humans before it has been proven safe. Although there is a robust debate over the merits of testing a drug on oneself before it has been approved by the FDA, Kung's colleagues -- and many other scientists -- believe that it is actually a thoroughly ethical thing to do.
   "For an investigator to inject himself first with his compound," says Mozley, "is highly ethical."
   That sensitive issue became even more sensitive in the wake of the University's firing of Dr. Mark Selikson, a former radiation safety officer, in February 1997. Selikson has since sued Penn for wrongful dismissal, claiming that he had been fired for alerting the FDA and the Nuclear Regulatory Commission about Kung's activities -- "utilizing radioactive compounds for human experimentation in a manner that violated federal regulations and University policy," in the words of the suit. The suit also charged that Penn, "seeking to protect its pecuniary interest in the fruits of the unlawful experimentation, responded by leveling a number of baseless allegations against Dr. Selikson" in order to justify the firing.
   
Penn strongly disputes the claim that he was fired for whistle-blowing, and says that Selikson was dismissed for other reasons, most of which had to do with his having allegedly defied University policy by doing consulting work for an outside firm and using University resources while doing so.
   "We believe [the lawsuit] is without merit," said Kenneth Wildes, Penn's director of news and public affairs, "and we will defend [the firing of Selikson] vigorously."
   Kung describes himself as "sort of a victim" of Selikson's lawsuit: "It had nothing to do with me, but I got dragged into it."
   But the medical possibilities of TRODAT, he says, should make up for all the trouble.
   "We are quite happy where we are," he said recently, "and I'm hopeful that this agent will be commercially available and will help various types of patients. And that's what makes all the headaches and troubles worthwhile in the end."
   
   
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Copyright 1999 The Pennsylvania Gazette Last modified 2/17/99