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
Routes of
administration 		Intravenous
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 C20H2518FN2O3
Molar mass 359g·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. The longer life allows 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

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. [9] [10]

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. [9]

Avid Radiopharmaceuticals was established 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. [11] Avid raised $500,000 from BioAdvance, a medically oriented venture capital firm in Pennsylvania, as seed funding toward the development of a biological marker. [12] 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. [9] [10]

Initial tests in 2007 on a patient at Johns Hopkins Hospital in Baltimore 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. [9]

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. [9]

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. [13] 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. [9]

In January 2011, 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. [14]

Approval by FDA

In January 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. [15]

Acquisition by Eli Lilly

Eli Lilly and Company announced in November 2010, that they would acquire Avid for $800 million. [16]

Related Research Articles

<span class="mw-page-title-main">Positron emission tomography</span> Medical imaging technique

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.

<span class="mw-page-title-main">Medical imaging</span> Technique and process of creating visual representations of the interior of a body

Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to reveal internal structures hidden by the skin and bones, as well as to diagnose and treat disease. Medical imaging also establishes a database of normal anatomy and physiology to make it possible to identify abnormalities. Although imaging of removed organs and tissues can be performed for medical reasons, such procedures are usually considered part of pathology instead of medical imaging.

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

Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera, but is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.

<span class="mw-page-title-main">Nuclear medicine</span> Medical specialty

Nuclear medicine, or nucleology, is a medical specialty involving the application of radioactive substances in the diagnosis and treatment of disease. Nuclear imaging is, in a sense, radiology done inside out, because it records radiation emitted from within the body rather than radiation that is transmitted through the body from external sources like X-ray generators. In addition, nuclear medicine scans differ from radiology, as the emphasis is not on imaging anatomy, but on the function. For such reason, it is called a physiological imaging modality. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) scans are the two most common imaging modalities in nuclear medicine.

<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.

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.

Fluorodeoxyglucose (<sup>18</sup>F) Chemical compound

[18F]Fluorodeoxyglucose (INN), or fluorodeoxyglucose F 18, also commonly called fluorodeoxyglucose and abbreviated [18F]FDG, 2-[18F]FDG or FDG, is a radiopharmaceutical, specifically a radiotracer, used in the medical imaging modality positron emission tomography (PET). Chemically, it is 2-deoxy-2-[18F]fluoro-D-glucose, a glucose analog, with the positron-emitting radionuclide fluorine-18 substituted for the normal hydroxyl group at the C-2 position in the glucose molecule.

Perfusion is the passage of fluid through the lymphatic system or blood vessels to an organ or a tissue. The practice of perfusion scanning is the process by which this perfusion can be observed, recorded and quantified. The term perfusion scanning encompasses a wide range of medical imaging modalities.

<span class="mw-page-title-main">Alzheimer's disease</span> Progressive neurodegenerative disease

Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is 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 with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years.

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.

<span class="mw-page-title-main">Brain positron emission tomography</span> Form of positron emission tomography

Brain positron emission tomography is a form of positron emission tomography (PET) that is used to measure brain metabolism and the distribution of exogenous radiolabeled chemical agents throughout the brain. PET measures emissions from radioactively labeled metabolically active chemicals that have been injected into the bloodstream. The emission data from brain PET are computer-processed to produce multi-dimensional images of the distribution of the chemicals throughout the brain.

Aducanumab, sold under the brand name Aduhelm, is a monoclonal antibody designed to treat Alzheimer's disease. It is a monoclonal antibody that targets aggregated forms (plaque) of amyloid beta (Aβ) found in the brains of people with Alzheimer's disease to reduce its buildup. It was developed by Biogen and Eisai. Aducanumab is given via intravenous infusion.

Radiofluorination is the process by which a radioactive isotope of fluorine is attached to a molecule and is preferably performed by nucleophilic substitution using nitro or halogens as leaving groups. Fluorine-18 is the most common isotope used for this procedure. This is due to its 97% positron emission and relatively long 109.8 min half-life. The half-life allows for a long enough time to be incorporated into the molecule and be used without causing exceedingly harmful effects. This process has many applications especially with the use of positron emission tomography (PET) as the aforementioned low positron energy is able to yield a high resolution in PET imaging.

Florbetaben, sold under the brand name Neuraceq, is a diagnostic radiotracer developed for routine clinical application to visualize β-amyloid plaques in the brain. It is a fluorine-18 (18F)-labeled stilbene derivative.

Flutemetamol (<sup>18</sup>F) Chemical compound

Flutemetamol (18F) is a PET scanning radiopharmaceutical containing the radionuclide fluorine-18, used as a diagnostic tool for Alzheimer's disease.

Flortaucipir (<sup>18</sup>F) Chemical compound

Flortaucipir (18F), sold under the brand name Tauvid, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) imaging to image the brain.

Donanemab, sold under the brand name Kisunla, is a monoclonal antibody used for the treatment of Alzheimer's disease. Donanemab was developed by Eli Lilly and Company.

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 (8 April 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 24 June 2010.
  7. ↑ Kolata G (23 June 2010). "Promise Seen for Detection of Alzheimer's". The New York Times . Archived from the original on 28 June 2010. Retrieved 23 June 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. 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.
  10. 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.
  11. ↑ "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.
  12. ↑ "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.
  13. ↑ Kolata G (12 July 2010). "New Scan May Spot Alzheimer's". The New York Times . Retrieved 14 July 2010.
  14. ↑ 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.
  15. ↑ Kolata G (30 January 2011). "F.D.A. Sees Promise in Alzheimer's Imaging Drug". The New York Times . Retrieved 20 January 2011.
  16. ↑ "Lilly Snags Avid Radiopharma". Forbes . 8 November 2010. Retrieved 8 November 2010.
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