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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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99mTc-Bis-amino-bis-thiol-conjugated 6-(3-bromopropoxy)-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one and (Z)-5-(3-bromopropoxy)-2-(4-(dimethylamino)benzylidene)benzofuran-3(2H)-one

[99mTc]BAT-FL, [99mTc]BAT-AR
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: December 28, 2011.

Chemical name:99mTc-Bis-amino-bis-thiol-conjugated 6-(3-bromopropoxy)-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one and (Z)-5-(3-bromopropoxy)-2-(4-(dimethylamino)benzylidene)benzofuran-3(2H)-oneImage BATFLAR99mTc.jpg
Abbreviated name:[99mTc]BAT-FL, [99mTc]BAT-AR
Synonym:
Agent Category:Compounds
Target:β-amyloid (Aβ)
Target Category:Accepters
Method of detection:Single-photon emission computed tomography (SPECT)
Source of signal / contrast:99mTc
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structures of [99mTc]BAT-FL and [99mTc]BAT-AR by Ono et al. (1).

Background

[PubMed]

99mTc-Bis-amino-bis-thiol (BAT)-conjugated 6-(3-bromopropoxy)-2-(4-(dimethylamino)phenyl)-4H-chromen-4-one and (Z)-5-(3-bromopropoxy)-2-(4-(dimethylamino)benzylidene)benzofuran-3(2H)-one, abbreviated as [99mTc]BAT-FL and [99mTc]BAT-AR, respectively, are flavone and aurone derivatives synthesized by Ono et al. for single-photon emission computed tomography (SPECT) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) (1).

AD is characterized in pathology by the presence of extracellular Aβ plaques, intraneuronal neurofibrillary tangles, and neuronal loss in the cerebral cortex (2, 3). Of them, Aβ deposit is the earliest neuropathological marker and is relatively specific to AD and closely related disorders. Aβ plaques are composed of abnormal paired helical filaments 5–10 nm in size. These filaments are largely made of insoluble Aβ peptides that are 40 or 42 amino acids in length (4).

In recent years, molecular imaging by targeting the extracellular Aβ has been intensively investigated in attempts to detect early AD, assess Aβ content in vivo, determine the timing of anti-plaque therapy, and evaluate the therapeutic efficacy (4). Radiolabeled Aβ40 peptides were tested first, but they showed poor penetration ability to cross the blood–brain barrier (BBB) (4). Based on the fact that Aβ can be specifically stained in vitro with dyes of Congo red, chrysamine G, and thioflavin-T, an effort was made to develop imaging agents with these dyes. This effort, however, was in general unsuccessful because the bulky ionic groups of heteroatoms in these dyes prevent them from crossing the BBB (2). Importantly, a large class of derivatives (e.g., aminonaphthalenes, benzothiazoles, stilbenes, and imidazopyridines) was synthesized with these dyes as templates (4). Clinical and preclinical studies have shown that these derivatives not only possess a high binding affinity with Aβ plaques as their parent compounds, but also exhibit good penetration ability through the BBB and rapid washout from brain with low to no plaque deposits.

Ono et al. first synthesized a class of radioiodinated flavone derivatives that present a high binding affinity with Aβ plaques and good penetration ability through the BBB (5). However, these flavone derivatives display poor clearance from the brain, which leads to a high brain background. The investigators then explored another class of flavonoids with aurone as the core structure (1, 6). Aurone is a heterocyclic chemical compound that contains a benzofuran element associated with a benzylidene linked in position 2 and a chalcone-like group closed into a five-member ring. The aurone derivatives possess a nucleophilic group (NH2, NHMe, or NMe2) at the 4' position and a radioiodine at the 5 position. Although these aurone derivatives exhibit a strong binding affinity with Aβ (inhibition constant (Ki) = 1.2–6.8 nM), high penetration ability through the BBB (1.9%−4.6% injected dose per gram tissue (ID/g) at 2 min), and a fast washout from the brain (0.3%−0.5% ID/g at 30 min), the pharmacokinetics of these compounds are less favorable for brain imaging than the pharmacokinetics of the agent [123I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine), which is the only SPECT agent to be tested in humans to date (7-9). The investigators also modified the flavone and aurone derivatives by pegylating them with 1–3 units of ethylene glycol at the 4' position or by conjugating them with the chelating agent bis-amino-bis-thiol (BAT). Favorable pharmacokinetics for brain imaging was observed for the pegylated derivatives ([18F]8(a–c)) but not for the BAT-chelated derivatives ([99mTc]BAT-FL and [99mTc]BAT-AR) (1, 6).

This series of chapters summarizes the data obtained with flavone and aurone derivatives, including [125I]15, [125I]9, [125I]14, [125I]16, [125I]17, [99mTc]BAT-FL, [99mTc]BAT-AR, [18F]8(a–c), [125I]3, and [18F]3 (1, 6-8). This chapter presents the data obtained with [99mTc]BAT-FL and [99mTc]BAT-AR (1).

Synthesis

[PubMed]

The synthesis of the compound precursors with chemical yields was described in detail by Ono et al. (1). [99mTc]BAT-FL and [99mTc]BAT-AR were prepared by a ligand exchange reaction with 99mTc-glucoheptonate. Both agents showed a single radioactive complex with a radiochemical purity of >95% after purification with high-performance liquid chromatography (HPLC). The retention times for [99mTc]BAT-FL and [99mTc]BAT-AR with HPLC (radioactivity) were 11.1 and 16.6 min, respectively. The radiochemical yields and specific activities for both agents were not reported. The log P values of [99mTc]BAT-FL and [99mTc]BAT-AR were 2.77 ± 0.04 and 2.23 ± 0.04, respectively.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The binding affinities of [99mTc]BAT-FL and [99mTc]BAT-AR were measured with Aβ(1−42) aggregates in solutions (1). The percent radioactivity of [99mTc]BAT-FL and [99mTc]BAT-AR bound to aggregates increased with increased dose of Aβ(1–42), while [99mTc]BAT without the flavone and aurone compounds showed no marked affinity for the aggregates. At all concentrations of Aβ aggregates, [99mTc]BAT-AR showed significantly greater affinity than [99mTc]BAT-FL. The nonspecific binding of [99mTc]BAT-FL and [99mTc]BAT-AR was estimated at 1.62%–1.85%. The affinities of [99mTc]BAT-FL and [99mTc]BAT-AR were less than those of 99mTc-labeled chalcone derivatives (e.g., 99mTc-BAT-chalcone or [99mTc]17) (10).

The binding of [99mTc]BAT-FL and [99mTc]BAT-AR with mouse Aβ plaques was confirmed with fluorescent staining in the brain sections of double transgenic AD mice (Tg2576) (1). Amyloid plaques were clearly stained with compound 3, and the labeling pattern was consistent with that observed with thioflavin S staining. Although [99mTc]BAT-AR showed greater affinity than [99mTc]BAT-AR in the in vitro binding assays, no binding difference was observed between [99mTc]BAT-FL and [99mTc]BAT-AR with fluorescent staining.

Animal Studies

Rodents

[PubMed]

The biodistribution of [99mTc]BAT-FL and [99mTc]BAT-AR was studied in normal mice (n = 3–6 mice/time point for each agent) (1). The initial brain uptake values for [99mTc]BAT-FL and [99mTc]BAT-AR were 0.64% ID/g and 0.79% ID/g at 2 min, and they decreased to 0.23% ID/g and 0.11% ID/g at 60 min after injection, respectively. Compared with that of the 99mTc-labeled chalcone derivative (99mTc-BAT-chalcone or [99mTc]17), the radioactivity of [99mTc]BAT-FL and [99mTc]BAT-AR in the brain appears insufficient for the imaging of Aβ plaques (1, 10). The results showed that the scaffolds of the [99mTc]BAT complexes did not play an important role in the affinity for Aβ aggregates and in the improvement of the pharmacokinetics of flavone and aurone derivatives.

Other Non-Primate Mammals

[PubMed]

No references are currently available.

Non-Human Primates

[PubMed]

No references are currently available.

Human Studies

[PubMed]

No references are currently available.

References

1.
Ono M., Ikeoka R., Watanabe H., Kimura H., Fuchigami T., Haratake M., Saji H., Nakayama M. 99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral beta-amyloid plaques. Bioorg Med Chem Lett. 2010;20(19):5743–8. [PubMed: 20797860]
2.
Ono M. Development of positron-emission tomography/single-photon emission computed tomography imaging probes for in vivo detection of beta-amyloid plaques in Alzheimer's brains. Chem Pharm Bull (Tokyo). 2009;57(10):1029–39. [PubMed: 19801854]
3.
Mathis C.A., Wang Y., Klunk W.E. Imaging beta-amyloid plaques and neurofibrillary tangles in the aging human brain. Curr Pharm Des. 2004;10(13):1469–92. [PubMed: 15134570]
4.
Vallabhajosula S. Positron emission tomography radiopharmaceuticals for imaging brain Beta-amyloid. Semin Nucl Med. 2011;41(4):283–99. [PubMed: 21624562]
5.
Ono M., Maya Y., Haratake M., Ito K., Mori H., Nakayama M. Aurones serve as probes of beta-amyloid plaques in Alzheimer's disease. Biochem Biophys Res Commun. 2007;361(1):116–21. [PubMed: 17644062]
6.
Ono M., Watanabe R., Kawashima H., Kawai T., Watanabe H., Haratake M., Saji H., Nakayama M. 18F-labeled flavones for in vivo imaging of beta-amyloid plaques in Alzheimer's brains. Bioorg Med Chem. 2009;17(5):2069–76. [PubMed: 19201614]
7.
Maya Y., Ono M., Watanabe H., Haratake M., Saji H., Nakayama M. Novel radioiodinated aurones as probes for SPECT imaging of beta-amyloid plaques in the brain. Bioconjug Chem. 2009;20(1):95–101. [PubMed: 19072219]
8.
Watanabe H., Ono M., Kimura H., Kagawa S., Nishii R., Fuchigami T., Haratake M., Nakayama M., Saji H. A dual fluorinated and iodinated radiotracer for PET and SPECT imaging of beta-amyloid plaques in the brain. Bioorg Med Chem Lett. 2011;21(21):6519–22. [PubMed: 21920750]
9.
Newberg A.B., Wintering N.A., Plossl K., Hochold J., Stabin M.G., Watson M., Skovronsky D., Clark C.M., Kung M.P., Kung H.F. Safety, biodistribution, and dosimetry of 123I-IMPY: a novel amyloid plaque-imaging agent for the diagnosis of Alzheimer's disease. J Nucl Med. 2006;47(5):748–54. [PubMed: 16644743]
10.
Ono M., Ikeoka R., Watanabe H., Kimura H., Fuchigami T., Haratake M., Saji H., Nakayama M. Synthesis and evaluation of novel chalcone derivatives with 99mTc/Re complexes as potential probes for detection of β-amyloid plaques. ACS Chemical Neuroscience. 2010;1:1598–607. [PMC free article: PMC3368688] [PubMed: 22778849]
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