Pittsburgh compound B
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|Pittsburgh compound B|
|Jmol-3D images||Image 1|
|Molar mass||256.32 g mol−1|
|Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)|
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Pittsburgh compound B (PiB) is a radioactive 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.
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 tangles, 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 synthesised charge neutral benzothiazoles 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, 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, was tested 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 by Henry Engler 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 US 7270800 , 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.
Published clinical research studies using PiB
|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, and C.A. Mathis||J Cereb Blood Flow Metab 25: 1528-1547|
- Klunk, W.E., et al., Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.[see comment]. Annals of Neurology, 2004. 55(3): p. 306-19.
- 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.