Florbetaben (18F) Explained

Drug Name:Florbetaben (18F)
Tradename:Neuraceq
Dailymedid:Florbetaben
Routes Of Administration:Intravenous
Atc Prefix:V09
Atc Suffix:AX06
Legal Ca:Rx-only
Legal Ca Comment:[1]
Legal Us:Rx-only
Legal Us Comment:[2]
Legal Eu:Rx-only
Legal Eu Comment:[3]
Cas Number:902143-01-5
Pubchem:11501341
Chemspiderid:9676143
Unii:TLA7312TOI
Chebi:79033
Synonyms:BAY-949172
Iupac Name:4--N-methylaniline
Chemical Formula:C21H2618FNO3
Molecular Weight:358.44
Molecular Weight Comment:g·mol−1
Smiles:CNC1=CC=C(C=C1)/C=C/C2=CC=C(C=C2)OCCOCCOCC[18F]
Stdinchi: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
Stdinchikey:NCWZOASIUQVOFA-FWZJPQCDSA-N

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.

Florbetaben was approved for medical use in the European Union, the United States, and South Korea in 2014.[4] [5] [6]

Medical uses

Florbetaben is indicated for Positron Emission Tomography (PET) imaging of β-amyloid neuritic plaque density in the brains of adults with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment.

Alzheimer's disease and amyloid-beta PET imaging

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.[11] [12]

Development program

Florbetaben binding to β-amyloid plaques on human brain samples was originally demonstrated in 2005.[13] Highly selective binding for β-amyloid over other proteins (e.g., tau and a-synuclein) has been demonstrated in vitro.[14] Initial single-center studies demonstrated the potential for florbetaben PET imaging to discriminate between AD patients and non-AD patients or healthy volunteers.[15] 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.[16] 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.[17] Longitudinal data of 45 patients with MCI indicated that florbetaben PET imaging may be useful to identify patients who will progress to AD.[18] 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.[19]

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). 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. 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%). There was no overall difference in the tolerability of florbetaben between different age populations. Repeated annual florbetaben injections showed no differences in the tolerability profile. Risks and side effects are addressed in the patient information leaflet. You may also ask your doctor or pharmacist for further information.

Further reading

Notes and References

  1. Web site: Neurological therapies . . 9 May 2018 . 13 April 2024.
  2. Web site: Neuraceq- florbetaben f 18 injection, solution . DailyMed . 30 April 2024 . 16 May 2024.
  3. Web site: European Medicines Agency (EMA) . Neuraceq EPAR . 20 February 2014 . 16 May 2024.
  4. News: Piramal Imaging, Neuraceq - Summary of product characteristics (Europe) . 2014 . European Medicines Agency (EMA) . 2 September 2015 . 24 September 2015 . https://web.archive.org/web/20150924011806/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002553/WC500162592.pdf . dead .
  5. Piramal Imaging SA and Ci-Co Healthcare Announce Commercial Approval of Neuraceq in Korea . 2015. Piramal Imaging . PR Newswire .
  6. Dinkelborg L . Company Profile: Piramal Imaging . Neurodegenerative Disease Management . 5 . 4 . 283–8 . August 2015 . 26295720 . 10.2217/NMT.15.26 .
  7. Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes . Acta Neuropathologica . 82 . 4 . 239–59 . 1991 . 1759558 . 10.1007/BF00308809 . 668690 .
  8. Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ . Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade . The Lancet. Neurology . 9 . 1 . 119–28 . January 2010 . 20083042 . 2819840 . 10.1016/S1474-4422(09)70299-6 .
  9. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH . 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 . May 2011 . 21514250 . 3312024 . 10.1016/j.jalz.2011.03.005 .
  10. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, DeKosky ST, Gauthier S, Selkoe D, Bateman R, Cappa S, Crutch S, Engelborghs S, Frisoni GB, Fox NC, Galasko D, Habert MO, Jicha GA, Nordberg A, Pasquier F, Rabinovici G, Robert P, Rowe C, Salloway S, Sarazin M, Epelbaum S, de Souza LC, Vellas B, Visser PJ, Schneider L, Stern Y, Scheltens P, Cummings JL . Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria . The Lancet. Neurology . 13 . 6 . 614–29 . June 2014 . 24849862 . 10.1016/S1474-4422(14)70090-0 . 1939828 . PDF .
  11. Beach TG, Monsell SE, Phillips LE, Kukull W . 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 . April 2012 . 22437338 . 3331862 . 10.1097/NEN.0b013e31824b211b .
  12. Doraiswamy PM, Sperling RA, Johnson K, Reiman EM, Wong TZ, Sabbagh MN, Sadowsky CH, Fleisher AS, Carpenter A, Joshi AD, Lu M, Grundman M, Mintun MA, Skovronsky DM, Pontecorvo MJ . Florbetapir F 18 amyloid PET and 36-month cognitive decline: a prospective multicenter study . Molecular Psychiatry . 19 . 9 . 1044–51 . September 2014 . 24614494 . 4195975 . 10.1038/mp.2014.9 .
  13. Zhang W, Oya S, Kung MP, Hou C, Maier DL, Kung HF . F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Abeta aggregates in the brain . Nuclear Medicine and Biology . 32 . 8 . 799–809 . November 2005 . 16253804 . 10.1016/j.nucmedbio.2005.06.001 .
  14. Fodero-Tavoletti MT, Brockschnieder D, Villemagne VL, Martin L, Connor AR, Thiele A, Berndt M, McLean CA, Krause S, Rowe CC, Masters CL, Dinkelborg L, Dyrks T, Cappai R . In vitro characterization of [18F]-florbetaben, an Aβ imaging radiotracer . Nuclear Medicine and Biology . 39 . 7 . 1042–8 . October 2012 . 22503458 . 10.1016/j.nucmedbio.2012.03.001 .
  15. Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O'Keefe G, Tochon-Danguy H, Chan G, Berlangieri SU, Jones G, Dickinson-Rowe KL, Kung HP, Zhang W, Kung MP, Skovronsky D, Dyrks T, Holl G, Krause S, Friebe M, Lehman L, Lindemann S, Dinkelborg LM, Masters CL, Villemagne VL . 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 . February 2008 . 18191617 . 10.1016/S1474-4422(08)70001-2 . 20087440 .
  16. Senda M, Sasaki M, Yamane T, Shimizu K, Patt M, Barthel H, Sattler B, Nagasawa T, Schultze-Mosgau M, Aitoku Y, Dinkelborg L, Sabri O . 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 . January 2015 . 25143073 . 4244559 . 10.1007/s00259-014-2890-8 .
  17. Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G, O'Keefe G, Ackerman U, Tochon-Danguy H, Chan JG, Reininger CB, Fels L, Putz B, Rohde B, Masters CL, Rowe CC . Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias . Journal of Nuclear Medicine . 52 . 8 . 1210–7 . August 2011 . 21764791 . 10.2967/jnumed.111.089730 . free .
  18. Ong KT, Villemagne VL, Bahar-Fuchs A, Lamb F, Langdon N, Catafau AM, Stephens AW, Seibyl J, Dinkelborg LM, Reininger CB, Putz B, Rohde B, Masters CL, Rowe CC . Aβ imaging with 18F-florbetaben in prodromal Alzheimer's disease: a prospective outcome study . Journal of Neurology, Neurosurgery, and Psychiatry . 86 . 4 . 431–6 . April 2015 . 24970906 . 10.1136/jnnp-2014-308094 . 25668886 .
  19. Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y, Senda K, Murayama S, Ishii K, Takao M, Beach TG, Rowe CC, Leverenz JB, Ghetti B, Ironside JW, Catafau AM, Stephens AW, Mueller A, Koglin N, Hoffmann A, Roth K, Reininger C, Schulz-Schaeffer WJ . Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: phase 3 study . Alzheimer's & Dementia . 11 . 8 . 964–74 . August 2015 . 25824567 . 10.1016/j.jalz.2015.02.004 . free .

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