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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
| Chemical name: | 2-{3-[18F]Fluoro-4-(methylamino)phenyl}-1,3-benzothiazol-6-ol |
|
| Abbreviated name: | [18F]Flutemetamol | |
| Synonym: | [18F]AH110690; [18F]-3'-F-6-OH-BTA1; [18F]-GE067 | |
| Agent Category: | Compound | |
| Target: | β-Amyloid plaque | |
| Target Category: | Protein | |
| Method of detection: | Positron emission tomography (PET) | |
| Source of signal / contrast: | 18F | |
| Activation: | No | |
| Studies: |
| Structure of [18F]flutemetamol. |
Rodents
Background
[PubMed]
Development of Alzheimer's disease (AD) has been attributed to neurodegeneration as a result of the neuronal overexpression, secretion, and deposition of the neurotoxic amyloid β (Aβ) fragment of the Aβ protein precursor in the brain (1). No specific treatment for AD is currently available, and clinicians are increasingly focused on developing ways to either prevent or delay the formation of Aβ plaques in the brain of AD patients (2). In addition, several hundred clinical trials approved by the United States Food and Drug Administration have been completed or are in progress to develop drugs for the prevention, onset delay, or treatment of AD. Early detection of Aβ plaques by noninvasive techniques such as positron emission tomography (PET) are often used to identify individuals who are prone to develop the disease and to monitor the efficacy of drugs used to treat or delay onset of the disease (3).
The 11C-labeled Pittsburgh compound B ([11C]PIB) is the most commonly used PET tracer for the detection of Aβ plaques, but the short half-life of 11C (20.4 min) restricts the use of this label to clinical facilities that have the capability to generate the probe on site (3). Some 18F-labeled compounds (half-life of 18F is ~110 min) have also been generated for the visualization of Aβ plaques, but these labeled compounds usually show low specificity toward the plaques (3). Investigators have synthesized some 18F-labeled PIB analogs, such as [18F]BAY94-9172 (4) and [18F]flutemetamol (2-{3-[18F]Fluoro-4-(methylamino)phenyl}-1,3-benzothiazol-6-ol) (5), earlier known as [18F]GE067 (6), and are evaluating these probes for the detection and diagnosis of AD in the clinic. Flutemetamol is a thioflavin T derivative of PIB and bears 18F-fluorine on the 3' position of the parent molecule (7). The biodistribution and PET imaging of Aβ plaques with [18F]flutemetamol have been investigated in rodents (8), healthy human volunteers (5, 6), and patients with mild cognitive impairment (7) and AD (5, 6).
Related Resource Links
Related chapters in MICAD
What is Alzheimer's disease (AD)?; Alzheimer's disease in Genetics Home Reference; Alzheimer's disease in Genome Wide Association Studies database
β-Amyloid (A4) precursor protein gene information (Gene ID 351)
Information on amyloidosis and related topics in Online Mendelian Inheritance in Man (OMIM) Database
Clinical trials related to β-amyloid plaques
Clinical trials related to [18F]flutemetamol
Amyloid inhibitors on U.S. Food and Drug Administration web site
Partial structure of β-amyloid protein (Protein Data Bank, NCBI)
FDA-approved treatments for Alzheimer's disease (from Alzheimer's Association web site; www.alz.org)
Synthesis
[PubMed]
Snellman et al. (8) synthesized [18F]flutemetamol according to a procedure similar to that described in patent WO 2007/020400 A1 (9). The specific activity (SA) of [18F]flutemetamol was reported to be 1,460 ± 1,160 GBq/μmol (54.02 ± 42.92 Ci/μmol) at the end of synthesis (EOS) and 980 ± 430 GBq/μmol (36.26 ± 15.91 Ci/μmol) at the time of injection. The radiochemical purity (RCP) of the purified product was >98%. The radiochemical yield (RCY) and stability of the tracer were not reported.
[11C]PIB was synthesized and used for comparison with [18F]flutemetamol in some studies (8). The SA of [11C]PIB was reported to be 50 ± 11 GBq/μmol (1.85 ± 0.41 Ci/μmol) at the EOS and 17 ± 5 GBq/μmol (0.63 ± 0.19 Ci/μmol) at the time of injection. The RCP of [11C]PIB was >95%, but the RCY and stability of the tracer were not reported.
Animal Studies
Rodents
[PubMed]
The biodistribution of [18F]flutemetamol was compared with that of [11C]PIB in Sprague-Dawley rats (8). The animals (n = 3–5 rats/time point for each tracer) were administered 36 ± 7 MBq (1.33 ± 0.26 mCi; 0.05 ± 0.02 ng/g body weight (BW)) [18F]flutemetamol or 32 ± 8 MBq (1.18 ± 0.3 mCi; 2.7 ± 1.2 ng/g BW) [11C]PIB through the tail vein, and the mice were euthanized at various time points ranging from 5 min postinjection (p.i.) to 60 min p.i. (for [11C]PIB) or 120 min p.i. (for [18F]flutemetamol). All organs of interest, including the brain, were harvested from the rodents to determine the uptake of radioactivity in the various tissues. Results obtained from this study were presented as percent of injected dose per gram tissue (% ID/g). Radioactivity from both [18F]flutemetamol and [11C]PIB was rapidly cleared from blood and the other peripheral organs. Maximum tracer accumulation at 5 min p.i. was detected in the liver, and later in the intestine and the kidney from 30 min p.i. to 60 min p.i. Very little 18F was detected in the bones, indicating that [18F]flutemetamol was not defluorinated while in circulation. With [18F]flutemetamol, the uptake of label in the brain peaked at 5 min p.i. (3.67 ± 1.69% ID/g), and the brain/blood (BB) ratio at this time point was 12.2, which decreased to 4.6 at 15 min p.i. and to 1.0 at 60 min p.i. The frontal cortex of the brain showed the highest accumulation of label (at 5 min p.i.), followed by the striatum (from 15 min p.i. to 60 min p.i.). The uptake of tracer with [11C]PIB peaked at 5 min p.i. in the brain, with a BB ratio of 4.4, which decreased to 2.4 at 15 min p.i. and to 1.1 at 60 min p.i.
Autoradiographic images of brain sections obtained from the animals showed that the clearance of [18F]flutemetamol, particularly from the white matter, was slower than that of [11C]PIB (8). From the images it was evident that the uptake of label from [11C]PIB was homogeneous in all areas of the brain, but with [18F]flutemetamol the accumulation of radioactivity was higher in the white matter than in the gray matter. With [18F]flutemetamol, the white matter/parietal cortex ratio increased from 0.6 at 5 min p.i. to 1.6 at 30 min p.i. and to 10.9 at 60 min p.i. For [11C]PIB, this ratio increased from 1.1 at 5 min p.i. to 3.7 at 30 min p.i. (the ratio at 60 min p.i. was not reported because there was very low uptake of label in the brain at this time point).
To confirm that [18F]flutemetamol and [11C]PIB targeted the Aβ deposits in the brains of transgenic mice that are prone to develop AD (Tg2576 mice), the animals were injected with the radiochemicals as before (8). The brains of the animals were removed, and brain sections were subject to ex vivo autoradiography as described elsewhere (8). The radiographic images showed that both tracers were bound to the Aβ deposits present in the pre-frontal cortex of the animals. Preincubation of the brain sections with nonradioactive PIB resulted in displacement of radioactivity from the Aβ plaques. This showed that both radiochemicals had a high binding specificity for the Aβ deposits in the brain. The location of the plaques visualized with the two tracers was confirmed by staining the same brain sections with thioflavin S and the 6E10 monoclonal antibody. Autoradiography of the sections revealed that the nonspecific binding of [18F]flutemetamol in the white matter of the brain was higher than that observed with [11C]PIB in the same regions.
From these studies, the investigators concluded that [18F]flutemetamol is probably suitable for the visualization of Aβ plaques in the brains of rodents (8).
Human Studies
[PubMed]
In a phase I clinical study, the biodistribution of [18F]flutemetamol was investigated in 6 healthy elderly human subjects (5 men and 1 woman; age range, 51–74 yrs) by Koole et al. (6). On average, the subjects received 121 MBq (~4.5 mCi) [18F]flutemetamol in the presence of 10 μg nonradioactive flutemetamol as a slow bolus injection through the antecubital vein. Whole-body PET scans were obtained from the individuals as described by van Laere et al. (10). From the images it was evident that the label was taken up by the brain (6%–8% ID/g) and the liver (~25% ID/g) at <5 min p.i., and the tracer was gradually lost from both of these organs by 5 h p.i. At 60 min p.i., the amount of radioactivity accumulated in the gall bladder was <1% ID/g for 2 patients and 5%–13% ID/g in the other 4 patients). The amount of label in the intestine at 60 min p.i. varied from ~2% ID/g (2 patients) to 20%–40% ID/g (4 patients), and in the urinary bladder the uptake was ~5% ID/g in all patients at this time point. For most patients, the accumulation of radioactivity gradually increased in the gall bladder, intestine, and the urinary bladder from 60 min p.i. to 5 h p.i. From this study, the investigators concluded that [18F]flutemetamol was safe to use in humans and was probably suitable for the imaging of Aβ plaques in the human brain (6).
In another phase I clinical study, the use of [18F]flutemetamol for the detection of AD in humans was investigated in 8 patients with clinical early-stage probable AD (6 men and 2 women; mean age, 68.8 yrs) and 8 healthy controls (5 men and 3 women; mean age, 62.5 yrs) (5). All participants in the study received a slow bolus injection of ~180 MBq (6.66 mCi) [18F]flutemetamol through the antecubital vein, and brain PET scans were acquired from the individuals as described elsewhere (5). It was observed that, after 80 min p.i., the neocortical to cerebral uptake was maximal in both groups and was not affected by the start time or duration of the scan. However, the AD patients showed significantly higher standardized uptake value ratios (SUVRs) in the neocortical association zones and the striatum compared with the controls. There was no difference in the uptake of radioactivity in the white matter, cerebellum, and pons of the brain between the two groups. Two patients with AD were false-negative with [18F]flutemetamol, and one control patient was false-positive with the tracer. From this study, the investigators concluded that the binding of [18F]flutemetamol in the human brain can be quantified, but further studies are necessary to validate its use as a biomarker for Aβ amyloidosis (5).
The efficacy of [18F]flutemetamol was compared with that of [11C]PIB for the imaging of AD and amnestic mild cognitive impairment (MCI) in a multicenter phase II clinical trial involving 27 patients with early-stage clinically probable AD, 20 individuals with MCI, and 15 healthy volunteers (7). The SUVRs for the AD and MCI subjects were determined and compared, and the test-retest variability of [18F]flutemetamol was determined in 5 of the AD patients. Results obtained from this study showed that SUVRs for the two probes were similar within the same subjects, and the Pearson correlation coefficients for the cortical region, lateral frontal region, striatum, and the subcortical white matter were 0.905, 0.924, 0.843, and 0.364, respectively. The test-retest variability of [18F]flutemetamol for the 5 AD patients ranged from 1% to 5%, indicating that there was a high test-retest reliability with this radiochemical. From this study, the investigators concluded that [18F]flutemetamol is probably well suited for the detection and diagnosis of AD in humans (7).
The correlation between PET imaging of Aβ plaques with [18F]flutemetamol and in vivo cerebral cortical histopathology was investigated in 7 patients with AD who had previously undergone biopsy for diagnosis of the disease (11). Each subject received a dose of ~185 MBq (6.84 mCi) [18F]flutemetamol, and whole-brain PET scans were obtained at ~90 min p.i. The investigators reported that there was a significant agreement (P = 0.01) between visual reads of the PET scans and the brain histopathology data of the patients. This indicated that [18F]flutemetamol has a high sensitivity for the detection of amyloid plaques.
In another [18F]flutemetamol PET imaging study with 12 patients of AD with normal pressure hydrocephalus, the brain uptake SUVRs correlated significantly (P = 0.0174) with the level of amyloid plaques observed with immunohistochemical staining (using the anti-amyloid 4 G8 monoclonal antibody) of brain biopsy samples of the patients (12).
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- Review 4-Hydroxy-, 5-hydroxy-, and 7-hydroxy- analogs of 6-hydroxy-2-(4’-[(11)C]methylaminophenyl)-1,3-benzothiazole.[Molecular Imaging and Contrast...]Review 4-Hydroxy-, 5-hydroxy-, and 7-hydroxy- analogs of 6-hydroxy-2-(4’-[(11)C]methylaminophenyl)-1,3-benzothiazole.Chopra A. Molecular Imaging and Contrast Agent Database (MICAD). 2004
- Review 5-[(18)F]Fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-oxazolo[5,4-b]pyridine.[Molecular Imaging and Contrast...]Review 5-[(18)F]Fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-oxazolo[5,4-b]pyridine.Chopra A. Molecular Imaging and Contrast Agent Database (MICAD). 2004
- Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer's disease.[Acta Neuropathol. 2020]Post-mortem analyses of PiB and flutemetamol in diffuse and cored amyloid-β plaques in Alzheimer's disease.Ikonomovic MD, Buckley CJ, Abrahamson EE, Kofler JK, Mathis CA, Klunk WE, Farrar G. Acta Neuropathol. 2020 Oct; 140(4):463-476. Epub 2020 Aug 9.
- Review Imaging β-amyloid using [(18)F]flutemetamol positron emission tomography: from dosimetry to clinical diagnosis.[Eur J Nucl Med Mol Imaging. 2016]Review Imaging β-amyloid using [(18)F]flutemetamol positron emission tomography: from dosimetry to clinical diagnosis.Heurling K, Leuzy A, Zimmer ER, Lubberink M, Nordberg A. Eur J Nucl Med Mol Imaging. 2016 Feb; 43(2):362-373. Epub 2015 Oct 6.
- Review Positron emission tomography radiopharmaceuticals for imaging brain Beta-amyloid.[Semin Nucl Med. 2011]Review Positron emission tomography radiopharmaceuticals for imaging brain Beta-amyloid.Vallabhajosula S. Semin Nucl Med. 2011 Jul; 41(4):283-99.
- 2-{3-[18F]Fluoro-4-(methylamino)phenyl}-1,3-benzothiazol-6-ol - Molecular Imagin...2-{3-[18F]Fluoro-4-(methylamino)phenyl}-1,3-benzothiazol-6-ol - Molecular Imaging and Contrast Agent Database (MICAD)
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