Florbetaben (18F)

Florbetaben, a fluorine-18 (18F)-labeled stilbene derivative (formerly known as BAY-949172), trade name NeuraCeq, is a diagnostic radiotracer developed for routine clinical application to visualize β-amyloid plaques in the brain. It is indicated for Positron Emission Tomography (PET) imaging of β-amyloid neuritic plaque density in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment. β-amyloid is a key neuropathological hallmark of AD, so markers of β-amyloid plaque accumulation in the brain are useful in distinguishing AD from other causes of dementia. The tracer successfully completed a global multicenter phase 0–III development program and obtained approval in Europe, US and South Korea in 2014.[1][2][3][4]

Florbetaben (18F)
Clinical data
Trade namesNeuraceq
Other namesBAY-949172
AHFS/Drugs.comFDA Professional Drug Information
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
  • 4-{(E)-2-[4-(2-{2-[2-(18F)Fluoroethoxy]ethoxy}ethoxy)phenyl]vinyl}-N-methylaniline
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H26FNO3
Molar mass358.44 g·mol−1
3D model (JSmol)
  • CNC1=CC=C(C=C1)/C=C/C2=CC=C(C=C2)OCCOCCOCC[18F]
  • InChI=1S/C21H26FNO3/c1-23-20-8-4-18(5-9-20)2-3-19-6-10-21(11-7-19)26-17-16-25-15-14-24-13-12-22/h2-11,23H,12-17H2,1H3/b3-2+/i22-1
  • Key:NCWZOASIUQVOFA-FWZJPQCDSA-N

Alzheimer's disease and amyloid-beta PET imaging

More than 44 million people worldwide have been diagnosed with some type of dementia, with two-thirds of this population likely to suffer from a mild, moderate or even severe form of AD. This number is expected to double by 2030 and triple by 2050.[5] Accurate diagnosis and early identification of cognitive and functional impairment due to AD and other etiologies are critical for optimization of patient care and initiation of appropriate therapies. Despite the importance of early and accurate detection of dementia, in practice, many individuals are misdiagnosed or remain even undiagnosed.[6]

The deposition of β-amyloid is considered as one hallmark in the pathogenesis of AD,[7] and most likely begins years before the onset of detectable cognitive symptoms.[8] Clinical testing using neuropsychology or memory examinations is the standard tool to diagnose AD as clinically possible or probable. Confirmation of the clinical diagnosis requires the identification of β-amyloid plaques in the brain. Until recently, this was only possible after death, in postmortem histopathology. The need of diagnosis confirmation during life has led to the development and incorporation of biomarkers, such as cerebrospinal fluid and amyloid imaging markers, as supplementary tools to facilitate clinical testing in the workflow of AD diagnosis.[9][10]

When used in conjunction with other clinical tests, florbetaben can assist in the diagnosis of AD by detecting the presence or absence of β-amyloid plaques. This is particularly relevant at the prodromal AD stage of mild cognitive impairment (MCI) and at the dementia stage of this disease, where clinical tests lack accuracy to establish a trustworthy AD diagnosis.[6][11]

Development program

Florbetaben binding to β-amyloid plaques on human brain samples was originally demonstrated in 2005.[12] Highly selective binding for β-amyloid over other proteins (e.g., tau and a-synuclein) has been demonstrated in vitro.[13] Initial single-center studies demonstrated the potential for florbetaben PET imaging to discriminate between AD patients and non-AD patients or healthy volunteers.[14] Single dose pharmacokinetics of 300 MBq florbetaben of low or high mass dose (<=5 and 50–55 μg) showed no relevant differences between Japanese and Caucasian populations.[15] When compared to healthy subjects, cortical uptake of florbetaben was demonstrated to be generally higher in a large proportion of patients with a clinical diagnosis of AD or mild cognitive impairment.[16] Longitudinal data of 45 patients with MCI indicated that florbetaben PET imaging may be useful to identify patients who will progress to AD.[17] A substantial proportion of patients with a positive florbetaben PET scan progressed to AD-dementia over a 2-year and 4-year time frame. At 4-year follow-up, 88% (21/24) of individuals with MCI and positive florbetaben uptake converted to clinical dementia due to AD, whereas none of 21 florbetaben-negative individuals with MCI experienced a conversion. The pivotal phase III study investigated the relationship of florbetaben imaging and amyloid deposition in the brain in patients with a clinical diagnosis of AD and other dementias and subjects without dementia.[18]

Florbetaben PET imaging showed strong tracer accumulation in the anatomically matched brain regions confirmed to have β-amyloid plaques by postmortem histopathology, thus providing direct target validation for florbetaben. Evaluation of whole brain florbetaben PET images using the clinically applicable visual assessment method demonstrated that florbetaben provides good diagnostic efficacy in detecting/excluding cerebral neuritic β-amyloid plaques. Sensitivity and specificity of the whole brain assessment was 98 and 89%, respectively, against the histopathological standard of truth. Good agreement between blinded readers (kappa 0.90) was reported. Furthermore, high negative and positive predictive values were reported for florbetaben imaging to exclude or detect β-amyloid plaques (negative predictive value 96.0% and positive predictive value 93.9%, see [18]). Intravenous injections of florbetaben are generally well tolerated in all subject groups. Analysis of 872 patients with 978 florbetaben administrations found no serious adverse reactions related to the tracer.[1] All adverse reactions reported were mild to moderate in severity and temporary only. The most common reactions (incidence < 1%) were injection-site pain (3.9% of patients), injection-site erythema (1.7%) and injection-site irritation (1.2%).[1] There was no overall difference in the tolerability of florbetaben between different age populations.[1] Repeated annual florbetaben injections showed no differences in the tolerability profile.[2] Risks and side effects are addressed in the patient information leaflet.[1][2] You may also ask your doctor or pharmacist for further information.

See also

References
  1. "Piramal Imaging, NeuraCeq - Prescribing Information (US) " (PDF). FDA. 2014.
  2. "Piramal Imaging, NeuraCeq - Summary of product characteristics (Europe) " (PDF). EMA. 2014.
  3. "Piramal Imaging, Piramal Imaging SA and Ci-Co Healthcare Announce Commercial Approval of Neuraceq in Korea 2015". PR Newswire. 2015.
  4. Dinkelborg L (August 2015). "Piramal Imaging". Neurodegenerative Disease Management. 5 (4): 283–8. doi:10.2217/NMT.15.26. PMID 26295720.
  5. Prince, M.; et al. (2014). "World Alzheimer Report 2014" (PDF). Alzheimer's Disease International.
  6. Beach TG, Monsell SE, Phillips LE, Kukull W (April 2012). "Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010". Journal of Neuropathology and Experimental Neurology. 71 (4): 266–73. doi:10.1097/NEN.0b013e31824b211b. PMC 3331862. PMID 22437338.
  7. Braak H, Braak E (1991). "Neuropathological stageing of Alzheimer-related changes". Acta Neuropathologica. 82 (4): 239–59. doi:10.1007/BF00308809. PMID 1759558. S2CID 668690.
  8. Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. (January 2010). "Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade". The Lancet. Neurology. 9 (1): 119–28. doi:10.1016/S1474-4422(09)70299-6. PMC 2819840. PMID 20083042.
  9. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. (May 2011). "The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease". Alzheimer's & Dementia. 7 (3): 263–9. doi:10.1016/j.jalz.2011.03.005. PMC 3312024. PMID 21514250.
  10. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. (June 2014). "Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria". The Lancet. Neurology. 13 (6): 614–29. doi:10.1016/S1474-4422(14)70090-0. PMID 24849862. S2CID 1939828.
  11. Doraiswamy PM, Sperling RA, Johnson K, Reiman EM, Wong TZ, Sabbagh MN, et al. (September 2014). "Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study". Molecular Psychiatry. 19 (9): 1044–51. doi:10.1038/mp.2014.9. PMC 4195975. PMID 24614494.
  12. Zhang W, Oya S, Kung MP, Hou C, Maier DL, Kung HF (November 2005). "F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Abeta aggregates in the brain". Nuclear Medicine and Biology. 32 (8): 799–809. doi:10.1016/j.nucmedbio.2005.06.001. PMID 16253804.
  13. Fodero-Tavoletti MT, Brockschnieder D, Villemagne VL, Martin L, Connor AR, Thiele A, et al. (October 2012). "In vitro characterization of [18F]-florbetaben, an Aβ imaging radiotracer". Nuclear Medicine and Biology. 39 (7): 1042–8. doi:10.1016/j.nucmedbio.2012.03.001. PMID 22503458.
  14. Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O'Keefe G, et al. (February 2008). "Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism". The Lancet. Neurology. 7 (2): 129–35. doi:10.1016/S1474-4422(08)70001-2. PMID 18191617. S2CID 20087440.
  15. Senda M, Sasaki M, Yamane T, Shimizu K, Patt M, Barthel H, et al. (January 2015). "Ethnic comparison of pharmacokinetics of (18)F-florbetaben, a PET tracer for beta-amyloid imaging, in healthy Caucasian and Japanese subjects". European Journal of Nuclear Medicine and Molecular Imaging. 42 (1): 89–96. doi:10.1007/s00259-014-2890-8. PMC 4244559. PMID 25143073.
  16. Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G, et al. (August 2011). "Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias". Journal of Nuclear Medicine. 52 (8): 1210–7. doi:10.2967/jnumed.111.089730. PMID 21764791.
  17. Ong KT, Villemagne VL, Bahar-Fuchs A, Lamb F, Langdon N, Catafau AM, et al. (April 2015). "Aβ imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study". Journal of Neurology, Neurosurgery, and Psychiatry. 86 (4): 431–6. doi:10.1136/jnnp-2014-308094. PMID 24970906. S2CID 25668886.
  18. Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y, et al. (August 2015). "Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: phase 3 study". Alzheimer's & Dementia. 11 (8): 964–74. doi:10.1016/j.jalz.2015.02.004. PMID 25824567.
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