Florbetapir (18F)

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Florbetapir (18F)
Florbetapir F-18.svg
Clinical data
Pronunciationflor bay' ta pir
Trade names Amyvid
Other names18F-AV-45, florbetapir-fluorine-18, Florbetapir F 18 [1] (USAN US)
AHFS/Drugs.com Micromedex Detailed Consumer Information
License data
ATC code
Legal status
Legal status
Identifiers
  • 4-[(E)-2-(6-{2-[2-(2-(18F)Fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)ethen-1-yl]-N-methylaniline
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H25FN2O3
Molar mass 360.429 g·mol−1
3D model (JSmol)
  • CNC1=CC=C(C=C1)/C=C/C2=CN=C(C=C2)OCCOCCOCC[18F]
  • InChI=1S/C20H25FN2O3/c1-22-19-7-4-17(5-8-19)2-3-18-6-9-20(23-16-18)26-15-14-25-13-12-24-11-10-21/h2-9,16,22H,10-15H2,1H3/b3-2+/i21-1
  • Key:YNDIAUKFXKEXSV-CRYLGTRXSA-N

Florbetapir (18F), sold under the brand name Amyvid, is a PET scanning radiopharmaceutical compound containing the radionuclide fluorine-18 that was approved for use in the United States in 2012, [4] as a diagnostic tool for Alzheimer's disease. [5] [6] [7] [8] Florbetapir, like Pittsburgh compound B (PiB), binds to beta-amyloid, however fluorine-18 has a half-life of 109.75 minutes, in contrast to PiB's radioactive half life of 20 minutes. Wong et al. found that the longer life allowed the tracer to accumulate significantly more in the brains of people with AD, particularly in the regions known to be associated with beta-amyloid deposits. [8]

Contents

One review predicted that amyloid imaging is likely to be used in conjunction with other markers rather than as an alternative. [9]

Development

Since the disease was first described by Alois Alzheimer in 1906, the only certain way to determine if a person indeed had the disease was to perform a biopsy on the patient's brain to find distinctive spots on the brain that show the buildup of amyloid plaque. Doctors must diagnose the disease in patients with memory loss and dementia based on symptoms, and as many as 20% of patients diagnosed with the disease are found after examination of the brain following death not to have had the condition. Other diagnostic tools, such as analysis of cerebrospinal fluid, magnetic resonance imaging scans looking for brain shrinkage and PET scans looking at how glucose was used in the brain, had all been unreliable. [10] [11]

The development of florbetapir built on research done by William Klunk and Chester Mathis who had developed a substance they called Pittsburgh compound B as a means of detecting amyloid plaque, after analyzing 400 prospective compounds and developing 300 variations of the substance that they had discovered might work. In 2002, a study performed in Sweden on Alzheimer's patients was able to detect the plaque in PET brain scans. Later studies on a control group member without the disease did not find plaque, confirming the reliability of the compound in diagnosis. While the tool worked, Pittsburgh compound B relies on the use of carbon-11, a radioactive isotope with a half-life of 20 minutes that requires the immediate use of the material prepared in a cyclotron. [10]

Avid Radiopharmaceuticals was established by Dr. Daniel Skovronsky in July 2005 with the goal of finding a isotope that could be injected into the body, would cross the blood–brain barrier and attach itself to amyloid protein deposits in the brain. [12] Avid raised $500,000 from BioAdvance, a medically oriented venture capital firm in Pennsylvania, as seed funding toward the development of a biological marker. [13] Once they found a candidate isotope, they attached the positron-emitting fluorine-18, a radioactive isotope with a half-life over five times longer (109.75 minutes), used in PET scans, and that can last for as long as a day when prepared in the morning by cyclotron. The isotope had been developed and patented by the University of Pennsylvania and was licensed by Avid. [10] [11]

Initial tests in 2007 on a patient at Johns Hopkins University Hospital previously diagnosed with symptoms of Alzheimer's disease detected plaque in a PET scan in areas where it was typically found in the brain. Further tests found that the scans detected plaque in patients with Alzheimer's, didn't find it in those without the diagnosis and found intermediate amounts in patients with early signs of dementia. The tests found amyloid plaque in 20% of its test patients over age 60 that had been in the normal range, but had performed worse than a control group on tests of mental acuity. [10]

Validation by autopsy

In order to confirm if the isotope was accurate in detecting Alzheimer's, an advisory committee at the Food and Drug Administration demanded that the team of Avid, Bayer and General Electric perform a study to test their method. Avid established a study with a group of 35 hospice patients, some that had been diagnosed with dementia and others that had no memory problems. The participants and their families agreed that they would undergo the PET scans and would have their brains autopsied after their death by pathologists. After the study was conducted, Avid received confirmation in May 2010 that the results of the test were successful in distinguishing between those with Alzheimer's and those without the disease. [10]

In results presented in July 2010, the company showed that for 34 out of the 35 hospice patients who had been scanned, the initial scan results were confirmed when pathologists counted plaque under a microscope and when a computerized scan of the plaque was performed on material from the autopsied brain. [14] The findings required review by the FDA to confirm their reliability as a means of diagnosing the disease. Once confirmed, the technique provided a means to reliably diagnose and monitor the progress of Alzheimer's and allowed potential pharmaceutical treatments to be evaluated. [10]

In a study published in January 2011 in the Journal of the American Medical Association , Avid reported on the results of further studies conducted based on 152 test subjects who had agreed to receive the company's PET scans and to have their brains analyzed after death for definitive determination of the presence of amyloid plaques. Of the patients included in the study, 29 who died had autopsies performed on their brains and in all but one the brain autopsy results matched the diagnosis based on the PET scan taken before death. Avid's technique is being used to test the efficacy of Alzheimer's disease treatments being developed by other pharmaceutical firms as a means of determining the ability of the drugs to reduce the buildup of amyloid protein in the brains of living subjects. [15]

Approval by FDA

On January 20, 2011, an FDA advisory committee unanimously recommended that Avid's PET scan technique be approved for use. The advisory committee included a qualification requiring Avid to develop clear guidelines establishing when the tests had spotted enough of the amyloid plaque to make a diagnosis of Alzheimer's, a task that Avid CEO Daniel M. Skovronsky stated could be resolved in several months. [16]

Acquisition by Eli Lilly

Avid Radiopharmaceuticals was based at the University City Science Center research campus in Philadelphia, Pennsylvania. The company was the first to bring to market an FDA-approved method that could directly detect the amyloid deposition hallmark pathology of Alzheimer's disease.

Eli Lilly and Company announced on November 8, 2010, that they would acquire Avid for $800 million, $300 million up front and the balance paid later. [17] Dr. Skovronsky joined the executive committee following the acquisition. [18]

Related Research Articles

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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, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body.

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<span class="mw-page-title-main">Single-photon emission computed tomography</span> Nuclear medicine tomographic imaging technique

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<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve, with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.

<span class="mw-page-title-main">Cerebral amyloid angiopathy</span> Disease of blood vessels of the brain

Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. The term congophilic is sometimes used because the presence of the abnormal aggregations of amyloid can be demonstrated by microscopic examination of brain tissue after staining with Congo red. The amyloid material is only found in the brain and as such the disease is not related to other forms of amyloidosis.

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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 florbetapir (18F). Florbetapir can be used to detect beta amyloid plaques in patients with memory problems using positron emission tomography (PET) scans, making the company the first to bring to market an FDA-approved method that can directly detect this hallmark pathology of Alzheimer's disease.

Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite study that aims to improve clinical trials for the prevention and treatment of Alzheimer's disease (AD). This cooperative study combines expertise and funding from the private and public sector to study subjects with AD, as well as those who may develop AD and controls with no signs of cognitive impairment. Researchers at 63 sites in the US and Canada track the progression of AD in the human brain with neuroimaging, biochemical, and genetic biological markers. This knowledge helps to find better clinical trials for the prevention and treatment of AD. ADNI has made a global impact, firstly by developing a set of standardized protocols to allow the comparison of results from multiple centers, and secondly by its data-sharing policy which makes available all at the data without embargo to qualified researchers worldwide. To date, over 1000 scientific publications have used ADNI data. A number of other initiatives related to AD and other diseases have been designed and implemented using ADNI as a model. ADNI has been running since 2004 and is currently funded until 2021.

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Hartmuth Christian Kolb is a German chemist. He is considered one of the founders of click chemistry.

References

  1. ↑ "Statement on a Nonproprietary Name Adopted by the USAN Council - FLORBETAPIR F 18" (PDF). United States Adopted Name (USAN) Drug Finder. American Medical Association . Retrieved 18 March 2022.
  2. ↑ "Amyvid- florbetapir f 18 injection, solution". DailyMed. Retrieved 12 January 2021.
  3. ↑ "Amyvid EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 12 January 2021.
  4. ↑ "Drug Approval Package: Amyvid (florbetapir F 18) NDA 202008". U.S. Food and Drug Administration. 3 May 2012. Retrieved 12 October 2021.
  5. ↑ Carpenter AP, Pontecorvo MJ, Hefti FF, Skovronsky DM (August 2009). "The use of the exploratory IND in the evaluation and development of 18F-PET radiopharmaceuticals for amyloid imaging in the brain: a review of one company's experience". The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 53 (4): 387–393. PMID   19834448.
  6. ↑ Leung K (April 8, 2010). "(E)-4-(2-(6-(2-(2-(2-(18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine [[18F]AV-45]". Molecular Imaging and Contrast Agent Database. PMID   20641982 . Retrieved 2010-06-24.
  7. ↑ Kolata G (June 23, 2010). "Promise Seen for Detection of Alzheimer's". The New York Times . Archived from the original on 28 June 2010. Retrieved June 23, 2010.
  8. 1 2 Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont V, Ravert HT, et al. (June 2010). "In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)". Journal of Nuclear Medicine. 51 (6): 913–920. doi:10.2967/jnumed.109.069088. PMC   3101877 . PMID   20501908.
  9. ↑ Rabinovici GD, Jagust WJ (2009). "Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo". Behavioural Neurology. 21 (1): 117–128. doi: 10.1155/2009/609839 . PMC   2804478 . PMID   19847050.
  10. 1 2 3 4 5 6 Kolata G (23 June 2010). "Promise Seen for Detection of Alzheimer's". The New York Times . Retrieved 23 June 2010.
  11. 1 2 "Avid Radiopharmaceuticals Initiates First Phase II Trial Of Novel Compound For Imaging Alzheimer's Disease". Medical News Today . 11 June 2008. Retrieved 23 June 2010.
  12. ↑ "Phila. start-up developing a way to test for Alzheimer's, Avid Radiopharmaceuticals has raised $26 million in new venture financing. Seeking a test for Alzheimer's". The Philadelphia Inquirer . 9 May 2007. Retrieved 23 June 2010.
  13. ↑ "Avid Radiopharmaceuticals Selected to Receive Seed Funding from BioAdvance; Funds to Be Used to Develop Molecular Imaging Tools for Alzheimer's Disease". Business Wire . 5 January 2005. Retrieved 23 June 2010.
  14. ↑ Kolata G (12 July 2010). "New Scan May Spot Alzheimer's". The New York Times . Retrieved 14 July 2010.
  15. ↑ Kolata G (18 January 2011). "Two Tests Could Aid in Risk Assessment and Early Diagnosis of Alzheimer's". The New York Times . Retrieved 19 January 2011.
  16. ↑ Kolata G (30 January 2011). "F.D.A. Sees Promise in Alzheimer's Imaging Drug". The New York Times . Retrieved 20 January 2011.
  17. ↑ "Lilly Snags Avid Radiopharma". Forbes . 8 November 2010. Retrieved 8 November 2010.
  18. ↑ "Daniel M. Skovronsky, M.D., Ph.D. | Eli Lilly and Company". www.lilly.com. Retrieved 2020-07-17.
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