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New Alzheimer's disease probes appear on the horizon

New Alzheimer's disease probes appear on the horizon

Researchers have discovered that three promising PET radiopharmaceutical agents for imaging amyloid plaques are targeted to two different types of surface receptors that potentially expand the amount of diagnostic information available for early Alzheimer's disease detection.

Dr. Hank F. Kung, a professor of radiology at the University of Pennsylvania, explained the implications of his recent findings at the 2004 Society of Molecular Imaging meeting in September. During the same session, Washington University professor of radiology Dr. Mark W. Mintun challenged a widely held theory about amyloid plaque as a cause of Alzheimer's, suggesting that radiopharmaceuticals designed to diagnose AD might be better suited for different roles.

Kung's findings apply initially to three agents that have thus far shown the most promise for measuring the presence and extent of neurotoxic amyloid beta-peptide (A-beta), a plaquelike aggregate that is seen in sections of the brain affected by advanced AD. One is 2-(4-(methylamino)phyenyl-6-hydroxybenzothiazole, commonly called PIB. It was developed by Chet Mathis, Ph.D., a professor of radiology and pharmaceutical sciences at the University of Pittsburgh.

Another is 1-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl] ethylidene malononitrile (FDDNP). Molecular pharmacology professor Dr. Jorge R. Barrio and colleagues in the department of molecular and medical pharmacology at the University of California, Los Angeles discovered this radiotracer.

The third agent, a novel stilbene derivative developed in Kung's lab, is 4-N-methylamino-4´-hydroxystilbene labeled with carbon-11 to produce C-11 SB-13.

A fluorine-18 FDG-PET protocol developed by Dr. Daniel H. Silverman at UCLA was the first noninvasive test to gain acceptance for diagnosing Alzheimer's disease. Medicare reimbursement for the procedure under specific conditions was approved in September 2004. FDG-PET uncovers AD by detecting abnormally low FDG metabolism indicative of cell death and a permanent loss of cognitive functions. Its limitations have encouraged researchers to look for new imaging techniques that will diagnose AD earlier and help monitor response to drug treatment. Research has focused on radiopharmaceuticals capable of penetrating the blood-brain barrier and selectively binding to amyloid plaque.

C-11 SB is the most recent product of numerous experiments in Kung's lab. The work leading to it began with iodine-125 IMSB. At that early stage, Kung learned that radiopharmaceuticals with very high binding rates could be designed for this application.

Mathis made two alterations to IMSB to create PIB, Kung said. A metal group was removed to neutralize pH, and an iodine molecule was added to aid blood-brain barrier penetration.

Experience with IMSB led to the development of TZDM at Penn. It demonstrated extremely good binding characteristics, but TZDM was too lipophilic to penetrate the brain and washed out of regions of interest too easily. These findings suggested the chemical features of I-125 IMPY, an iodinated compound that has shown highly specific binding to A-beta aggregates in transgenic mouse studies.

I-125 IMPY WORK CONTINUES

Although work with I-125 IMPY continues, Kung and his colleagues appear to have improved on its performance with the creation of SB-13. Its first trial in humans produced results almost identical to those observed with C-11 PIB. (American Journal of Geriatric Psychiatry 2004[6]:584-595). High rates of uptake were measured for both agents in the frontal and posterior temporal-inferior parietal cortices of five AD patients.

Additional work strongly suggests that PIB and SB-13 are targeted to the same A-beta binding sites.

"The most important thing is that two entirely different chemical ligands produce very similar results, so we think we are looking at the same binding site," Kung said.

The uptake pattern of F-18 FDDNP is considerably different, however, which suggests to Kung that it binds either to a different receptor or to an additional receptor on the plaque's surface.

"Mother Nature has not been kind to give us this disease, but she at least has provided us with the hope that we can detect it with specific probes that bind to these pockets of aggregated amyloid," he said.

Kung's conclusions are based on the widely held assumption that amyloid plaques cause the neurological damage manifested in Alzheimer's disease. Mintun argued for an alternative theory at the SMI meeting, where he presented evidence showing that neurofibrillary tangles (NFTs) containing Tau proteins may be the actual culprit.

AMYLOID AND AD DIAGNOSIS

Although tangles and plaques are nearly always present in patients with advanced Alzheimer's, high concentrations of amyloid alone does not mean a person has the condition, Mintun said. He cited evidence collected at Washington University by Dr. John C. Morris and Joseph L. Price, Ph.D. Their autopsy data found that only 25% of the subjects with high concentrations of brain amyloid exhibited AD symptoms before their deaths. They concluded that this group represents a presymptomatic stage of Alzheimer's pathology.

"In other words, if amyloid plaques are a hallmark of Alzheimer's, they appear before clinical symptoms are manifested," Mintun said.

Based on these observations, amyloid plaque imaging may be well suited for identifying asymptomatic individuals at risk for developing Alzheimer's and for ruling out the diagnosis of AD in patients with mild cognitive dysfunction, Mintun said. If amyloid imaging can quantify plaque load as expected, it will also play an important role in monitoring the effect of antiamyloid therapies.

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