Pittsburgh Compound B
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Pittsburgh compound B (PiB) is a
radioactive Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is conside ...
analog of thioflavin T, which can be used in
positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
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 (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
.


History

The definitive diagnosis of Alzheimer's disease can only be made following the demonstration of the presence of beta-amyloid (Aβ) plaques and
neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
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 In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
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 The University of Pittsburgh (Pitt) is a Commonwealth System of Higher Education, state-related research university in Pittsburgh, Pennsylvania, United States. The university is composed of seventeen undergraduate and graduate schools and colle ...
led by
geriatrics Geriatrics, or geriatric medicine, is a medical specialty focused on addressing the unique health needs of older adults. The term ''geriatrics'' originates from the Greek γέρων ''geron'' meaning "old man", and ιατρός ''iatros'' mean ...
psychiatrist A psychiatrist is a physician who specializes in psychiatry. Psychiatrists are physicians who evaluate patients to determine whether their symptoms are the result of a physical illness, a combination of physical and mental ailments or strictly ...
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 Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
imaging agent. One of these compounds, 2-(4'- sup>11Cethylaminophenyl)-6-hydroxybenzothiazole, was tested in human subjects. The University of Pittsburgh team partnered with a team of researchers from
Uppsala University Uppsala University (UU) () is a public university, public research university in Uppsala, Sweden. Founded in 1477, it is the List of universities in Sweden, oldest university in Sweden and the Nordic countries still in operation. Initially fou ...
in
Uppsala Uppsala ( ; ; archaically spelled ''Upsala'') is the capital of Uppsala County and the List of urban areas in Sweden by population, fourth-largest city in Sweden, after Stockholm, Gothenburg, and Malmö. It had 177,074 inhabitants in 2019. Loc ...
,
Sweden Sweden, formally the Kingdom of Sweden, is a Nordic countries, Nordic country located on the Scandinavian Peninsula in Northern Europe. It borders Norway to the west and north, and Finland to the east. At , Sweden is the largest Nordic count ...
, 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 Uppsala University (UU) () is a public university, public research university in Uppsala, Sweden. Founded in 1477, it is the List of universities in Sweden, oldest university in Sweden and the Nordic countries still in operation. Initially fou ...
. PET scans showed that the compound was retained in areas of the
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...
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 other research institutions. In addition, GE Healthcare is pursuing the development of a clinical diagnostic agent based on PiB for assessing brain
amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weigh ...
.


Alzheimer's disease research

11C-PiB is currently the most studied and used radioligand for PET imaging of cerebral Aβ pathology. This technique has been implicated in Alzheimer's disease research whereby scientists involved in this field are able to perform noninvasive ''in vivo'' neuroimaging studies using PET scans in brains of individuals with various degrees of dementia. The 11C-Pittsburgh compound B (11C-PiB) radiotracer is used to measure regional 11C-PiB binding retention rates, thus allowing for the visual and quantitative measurement of Aβ deposition. 11C-PiB is a fluorescent derivative of thioflavin T which preferentially targets and binds to fibrillar Aβ forms found in dense core plaques with high affinity and specificity. In particular, it specifically binds to Aβ40 and Aβ42 fibrils and insoluble plaques containing the aforementioned Aβ peptides. PiB does not bind with great affinity to soluble or nonfibrillar Aβ plaques until plaques have reached a crucial magnitude, which has yet to be determined. Furthermore, this radiotracer does not bind to
neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...
s (NFTs) in the neuronal regions of the brain during postmortem autopsies. A typical injected dose ranges from 250 to 450 MBq and the imaging time normally varies between 40 and 90 minutes. The quantification of 11C-PiB has demonstrated to elicit a profound difference in neuronal cortical binding between individuals recognized with Alzheimer's disease and age-matched cognitively normal controls.


Published clinical research studies


See also

* Florbetapir * Florbetaben * Flutemetamol * Tafamidis * List of PET radiotracers


References


Further reading

* . Brain amyloid can be shown by staining brain sections with thioflavin S or Congo red. * . Some azo dyes such as Congo red, may be carcinogenic. * Intestinal bacteria convert Congo red to carcinogenic free amine. {{University of Pittsburgh Medical Center Alzheimer's disease Benzothiazoles Hydroxyarenes University of Pittsburgh