Pittsburgh compound B
Encyclopedia
Pittsburgh compound B is a fluorescent analog of thioflavin T, which can be used in positron emission tomography
scans to image beta-amyloid plaques in neuronal tissue. Due to this property, Pittsburgh compound B may be used in investigational studies of Alzheimer's disease
.
s, the pathologic hallmarks of Alzheimer's disease in brain tissue, typically at autopsy. While the cognitive impairments of the disease could be monitored throughout the disease course, clinicians had no reliable way to monitor the pathologic progression of the disease. Due to this fact, a clear understanding of the process of amyloid deposition and how amyloid deposits relate to the cognitive symptoms of Alzheimer's disease remains to be elucidated. While sophisticated centers for the treatment of Alzheimer's disease are able to diagnose the disease with some reliability based on its clinical presentation, the differential diagnosis
of Alzheimer's disease from other dementias is less robust. Furthermore, as novel disease-modifying therapies for Alzheimer's disease that attack and remove beta-amyloid deposits from the brain enter clinical trials, a pre-mortem tool for assessing their effectiveness at clearing the amyloid deposits was a much needed development.
To answer these needs, a research team from the University of Pittsburgh
led by geriatric psychiatrist William E. Klunk and radiochemist Chester A. Mathis identified a class of neutrally charged benzothiazole
s derived from thioflavin T, which included a small number of compounds with suitable properties for use as a positron emission tomography
imaging agent. One of these compounds, [N-methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, emerged as the lead agent to develop in human subjects. The University of Pittsburgh
team partnered with a team of researchers from Uppsala University
in Uppsala
, Sweden
, to conduct the first trials of this new agent in human research subjects. As this was the second investigational compound of this class sent to Uppsala from the University of Pittsburgh
group, it was termed simply Pittsburgh compound-B by the Swedish team, who also abbreviated it as "PiB".
The first PiB study of a human subject with a clinical diagnosis of Alzheimer's disease was conducted in February, 2002, at Uppsala University
. PET scans showed that the compound was retained in areas of the cerebral cortex
known to contain significant amyloid deposits from post-mortem examinations. The initial human study of PiB was expanded to include 16 Alzheimer's disease subjects and 9 cognitively normal controls, the report of which was published in 2004 in the Annals of Neurology.
Since that initial study, PiB has been adopted as a research tool by dozens of research institutions around the world. PiB and other compounds in its class are protected under , issued Sept. 18, 2007, which is presently assigned to the University of Pittsburgh
. The technology is under license to GE Healthcare
, a subsidiary of General Electric
, who is pursuing the development of a clinical diagnostic agent based on PiB for assessing brain amyloidosis
.
Avid Radiopharmaceuticals
of Philadelphia has developed a compound called 18F-AV-45 that uses the longer-lasting radionuclide fluorine-18
to detect amyloid plaques using PET scans.
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
scans to image beta-amyloid plaques in neuronal tissue. Due to this property, Pittsburgh compound B may be used in investigational studies of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
History of PiB
The definitive diagnosis of Alzheimer's disease can only be made following the demonstration of the presence of beta-amyloid plaques and neurofibrillary tangleNeurofibrillary tangle
Neurofibrillary Tangles are aggregates of hyperphosphorylated tau protein that are most commonly known as a primary marker of Alzheimer's Disease. Their presence is also found in numerous other diseases known as Tauopathies...
s, the pathologic hallmarks of Alzheimer's disease in brain tissue, typically at autopsy. While the cognitive impairments of the disease could be monitored throughout the disease course, clinicians had no reliable way to monitor the pathologic progression of the disease. Due to this fact, a clear understanding of the process of amyloid deposition and how amyloid deposits relate to the cognitive symptoms of Alzheimer's disease remains to be elucidated. While sophisticated centers for the treatment of Alzheimer's disease are able to diagnose the disease with some reliability based on its clinical presentation, the differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
of Alzheimer's disease from other dementias is less robust. Furthermore, as novel disease-modifying therapies for Alzheimer's disease that attack and remove beta-amyloid deposits from the brain enter clinical trials, a pre-mortem tool for assessing their effectiveness at clearing the amyloid deposits was a much needed development.
To answer these needs, a research team from the University of Pittsburgh
University of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...
led by geriatric psychiatrist William E. Klunk and radiochemist Chester A. Mathis identified a class of neutrally charged benzothiazole
Benzothiazole
Benzothiazole is an aromatic heterocyclic compound with the chemical formula . It is colorless, slightly viscous liquid. Although the parent compound, benzothiazole is not widely used, many of its derivatives are found in commercial products or in nature...
s derived from thioflavin T, which included a small number of compounds with suitable properties for use as a positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
imaging agent. One of these compounds, [N-methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, emerged as the lead agent to develop in human subjects. The University of Pittsburgh
University of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...
team partnered with a team of researchers from Uppsala University
Uppsala University
Uppsala University is a research university in Uppsala, Sweden, and is the oldest university in Scandinavia, founded in 1477. It consistently ranks among the best universities in Northern Europe in international rankings and is generally considered one of the most prestigious institutions of...
in Uppsala
Uppsala
- Economy :Today Uppsala is well established in medical research and recognized for its leading position in biotechnology.*Abbott Medical Optics *GE Healthcare*Pfizer *Phadia, an offshoot of Pharmacia*Fresenius*Q-Med...
, Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
, to conduct the first trials of this new agent in human research subjects. As this was the second investigational compound of this class sent to Uppsala from the University of Pittsburgh
University of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...
group, it was termed simply Pittsburgh compound-B by the Swedish team, who also abbreviated it as "PiB".
The first PiB study of a human subject with a clinical diagnosis of Alzheimer's disease was conducted in February, 2002, at Uppsala University
Uppsala University
Uppsala University is a research university in Uppsala, Sweden, and is the oldest university in Scandinavia, founded in 1477. It consistently ranks among the best universities in Northern Europe in international rankings and is generally considered one of the most prestigious institutions of...
. PET scans showed that the compound was retained in areas of the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
known to contain significant amyloid deposits from post-mortem examinations. The initial human study of PiB was expanded to include 16 Alzheimer's disease subjects and 9 cognitively normal controls, the report of which was published in 2004 in the Annals of Neurology.
Since that initial study, PiB has been adopted as a research tool by dozens of research institutions around the world. PiB and other compounds in its class are protected under , issued Sept. 18, 2007, which is presently assigned to the University of Pittsburgh
University of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...
. The technology is under license to GE Healthcare
GE Healthcare
GE Healthcare is a division of GE Technology Infrastructure, which is itself a division of General Electric . It employs more than 46,000 people worldwide and is headquartered in Little Chalfont, Buckinghamshire, United Kingdom. GE Healthcare is the first GE business segment to be headquartered...
, a subsidiary of General Electric
General Electric
General Electric Company , or GE, is an American multinational conglomerate corporation incorporated in Schenectady, New York and headquartered in Fairfield, Connecticut, United States...
, who is pursuing the development of a clinical diagnostic agent based on PiB for assessing brain amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
.
Avid Radiopharmaceuticals
Avid Radiopharmaceuticals
Avid Radiopharmaceuticals is an American company, founded by Dr. Daniel Skovronsky, and based at the University City Science Center research campus in Philadelphia, Pennsylvania. The company has developed a radioactive tracer called 18F-AV-45...
of Philadelphia has developed a compound called 18F-AV-45 that uses the longer-lasting radionuclide fluorine-18
Fluorine-18
Fluorine-18 is a fluorine radioisotope which is an important source of positrons. It has a mass of 18.0009380 u and its half-life is 109.771 minutes....
to detect amyloid plaques using PET scans.
Published clinical research studies using PiB
| Year | Title | Summary | Authors | Journal |
|---|---|---|---|---|
| 2004 | Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B | Retention of [C-11]PiB shown to be approximately 2-fold greater in cortical areas of AD subjects relative to controls. Pattern of retention mirrors the pattern of amyloid deposition known from post-mortem studies. | Klunk, W.E., H. Engler, A. Nordberg, Y. Wang, G. Blomqvist, D.P. Holt, M. Bergstrom, I. Savitcheva, G.F. Huang, S. Estrada, B. Ausen, M.L. Debnath, J. Barletta, J.C. Price, J. Sandell, B.J. Lopresti, A. Wall, P. Koivisto, G. Antoni, C.A. Mathis, and B. Langstrom | Ann Neurol 55:306-19 |
| 2005 | Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. | Metholodogy paper describing appropriate methods for the quantification of PiB brain scans. First report using PiB in subjects categorized with mild cognitive impairment (MCI). | Price, J.C., W.E. Klunk, B.J. Lopresti, X. Lu, J.A. Hoge, S.K. Ziolko, D.P. Holt, C.C. Meltzer, S.T. DeKosky Steven T. DeKosky Steven T. DeKosky is a medical researcher and academic known for his work in the field of Alzheimer's disease. DeKosky has served as professor and chairman of the Department of Neurology and director of the Alzheimer's Disease Research Center at the University of Pittsburgh... , and C.A. Mathis |
J Cereb Blood Flow Metab 25: 1528-1547 |
Further reading
- Puchtler et al., J. Histochem. Cytochem. 10: 35 (1962). Brain amyloid can be shown by staining brain sections with thioflavin S or Congo red.
- Morgan et al. Environmental Health Perspectives, 102 (supp.) 2: 63-78, (1994). Some azo dyes such as Congo red, may be carcinogenic.
- Cemiglia et al., Biochem. Biophys. Res. Com., 107: 1224-1229, (1982). Intestinal bacteria convert Congo red to carcinogenic free amine.