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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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Radioiodinated (1E,4E)-1-(4-aminophenyl)-5-(4-iodophenyl)penta-1,4-dien-3-one and (1E,4E)-1-(4-iodophenyl)-5-(4-(methylamino)phenyl)penta-1,4-dien-3-one

[125I]70, [125I]71
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: February 7, 2012.

Chemical name:Radioiodinated (1E,4E)-1-(4-aminophenyl)-5-(4-iodophenyl)penta-1,4-dien-3-one and (1E, 4E)-1-(4-iodophenyl)-5-(4-(methylamino)phenyl)penta-1,4-dien-3-oneImage I1257071.jpg
Abbreviated name:[125I]70, [125I]71
Synonym:
Agent Category:Compounds
Target:β-amyloid (Aβ)
Target Category:Accepters
Method of detection:Single-photon emission computed tomography (SPECT) or planar imaging
Source of signal / contrast:125I
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Structures of [125I]70 and [125I]71 by Cui et al. (1).

Background

[PubMed]

Radioiodinated (1E,4E)-1-(4-aminophenyl)-5-(4-iodophenyl)penta-1,4-dien-3-one (compound 70) and (1E, 4E)-1-(4-iodophenyl)-5-(4-(methylamino)phenyl)penta-1,4-dien-3-one (compound 71), abbreviated as [125I]70 and [125I]71, respectively, are two dibenzylideneacetone derivatives synthesized by Cui et al. for single-photon emission computed tomography (SPECT) of Alzheimer’s disease (AD) by targeting β-amyloid (Aβ) plaques (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). Aβ peptides have been shown to be toxic to neurons, and the level of Aβ peptides is closely correlated with the cognitive decline in AD. These features of Aβ prompted investigators to develop Aβ-targeted agents for AD imaging.

Curcumin is the principal component of the Indian spice turmeric, and in structure it is composed of two aromatic rings connected by two α,β-unsaturated carbonyl groups (1). In 2001, investigators at the University of California, Los Angeles, reported that curcumin is effective against neurodegeneration, oxidative damage, and diffuse plaque deposition after Aβ infusion in animals (5, 6). The anti-AD effect of curcumin has been further demonstrated to be partially due to its specific binding with Aβ, whereby it could break apart Aβ aggregates. In 2006, Ryu et al. tested eight curcumin derivatives as Aβ-specific imaging probes (7). In general, these derivatives are poor in brain–blood barrier (BBB) penetration and are unstable in vivo (1, 7). The curcumin derivatives are quickly converted to unidentified polar products, which cannot cross the BBB. The methylene moiety between the two aromatic rings is responsible for the poor stability, whereas the two aromatic rings are responsible for the binding with Aβ plaques. To improve the stability and BBB-penetrating ability of curcumin, various modifications on the curcumin structure have recently been made, including deleting the active methylene moiety in the middle of its structure (1).

Cui et al. synthesized a series of dibenzylideneacetones by deleting the methylene moiety and one carbonyl moiety and further linking various substituents on one (forming an asymmetrical structure) or on both aromatic rings (forming a symmetrical structure) (1). Analysis of the structure–affinity relationship among these derivatives has shown that dibenzylideneacetone without any substituents have a weak affinity with Aβ (inhibition constant (Ki) = 242.5 ± 42.8 nM). Introduction of Cl or methoxy groups at the para position on both phenyl rings to form symmetrical ligands can significantly increase the binding affinity (~90 folds), and the size of substituents has no effect on the affinity for Aβ aggregates. Methylation of a primary amino group to form a secondary or tertiary amino group can also significantly increase the affinity (e.g., the agents [125I]70 and [125I]71 described in this chapter), but methylation of the amino group at the ortho position reduces the binding affinity dramatically. Increasing the substituent size at the aromatic amino group also leads to decreased binding affinity. However, when a phenyl ring in the dibenzylideneacetone structure is changed to a heterocyclic ring, such as a thiophene, furan, pyridine, or pyrrole ring, the generated compounds maintain the high binding affinity. These results demonstrate that the para position is highly tolerant of steric bulk substitutions, which opens up the possibility of developing new, easily labeled radioligands for imaging Aβ plaques in vivo (1).

This chapter summarizes the data obtained with [125I]70 and [125I]71, two asymmetrical dibenzylideneacetones with methylation of a primary amino group at the para position (1). Another chapter summarizes the data obtained with [18F]83 and [18F]85, two fluoro-pegylated dibenzylideneacetones.

Synthesis

[PubMed]

Synthesis of compounds 70 and 71 was described in detail by Cui et al. (1). The radioiodinated ligands [125I]70 and [125I71 were prepared from the corresponding tributyltin precursors through iododestannylation reaction with hydrogen peroxide as an oxidant. The two agents were purified, and their radiochemical identities were verified with high-performance liquid chromatography. For the final products [125I]70 and [125I]71, their radiochemical yields were 15.3% and 24.1%, respectively, and their radiochemical purities were >98%. The specific activity of the no carrier-added preparation was comparable to that of Na125I (2,200 Ci/mmol (81.4 TBq/mmol)). The partition coefficients of [125I]70 and [125I71 were 3.26 and 3.55, respectively, indicating that both agents were lipophilic.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The binding affinity of unlabeled compounds 70 and 71 for Aβ142 was examined with [125I]IMPY (6-iodo-2-(4'-dimethylamino)phenyl-imidazo[1,2]pyridine) as the competing radioligand (1, 8). The Ki values of compounds 70 and 71 were 7.0 ± 2.2 nM and 2.8 ± 0.5 nM, respectively, which was superior to the binding affinity of IMPY (Ki = 10.5 nM) (8).

The binding of [125I]71 to Aβ plaques in brain tissue sections of transgenic mice (APP/PS1) was evaluated in vitro with autoradiography (1). Similar to the findings obtained from staining in human AD brain tissue sections, [125I]71 showed specific binding with Aβ plaques (refer to the Human Studies section). No data were reported for [125I]70.

Cui at al. also evaluated the in vitro binding of [125I]71 to Aβ plaques in human AD brain tissue sections with autoradiography (1). [125I]71 exhibited intensive labeling of the plaques, showing strong signal in the cortex region and low background level in the white matter in the AD brain sections. The hot spots of radioactivity were consistent with the results of immunohistochemical staining in the same sections using the Aβ antibody BC05. No data were reported for [125I]70.

Animal Studies

Rodents

[PubMed]

Biodistribution studies were performed in normal mice with [125I]70 and [125I]71 (n = 4 mice/time point for each agent) (1). Both [125I]70 and [125I]71 exhibited good penetration of the BBB with excellent initial uptake in the brain (4.56% and 4.68% injected dose per gram tissue (ID/g) at 2 min, respectively), showing improved initial uptake than the previously reported radiofluorinated curcumin (0.52% ID/g at 2 min) (7). The radioactivity was then washed out rapidly (0.54% and 0.71% ID/g at 60 min for [125I]70 and [125I]71, respectively). The brain2min/brain60min ratios were 8.44 and 6.59 for [125I]70 and [125I]71, respectively.

The thyroid uptake values for [125I]70 and [125I]71 reached 14.14% and 23.96% ID/g at 1 h, respectively, suggesting deiodination of the two agents in vivo. The two agents were cleared predominantly via the hepatobiliary system (24.17% and 23.88% ID/g in the liver at 30 min for [125I]70 and [125I]71, respectively), and the clearance was fast (25.97%–23.62% ID/g in the intestine at 60 min for [125I]70 and [125I]71, respectively). A moderate uptake of [125I]70 and [125I]71 was also observed in the kidneys (16.31% and 15.54% ID/g at 30 min, respectively), indicating that they were also excreted via the renal system.

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.
Cui M. et al. Synthesis and structure-affinity relationships of novel dibenzylideneacetone derivatives as probes for beta-amyloid plaques. J Med Chem. 2011;54(7):2225–40. [PubMed: 21417461]
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.
Frautschy S.A. et al. Phenolic anti-inflammatory antioxidant reversal of Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging. 2001;22(6):993–1005. [PubMed: 11755008]
6.
Lim G.P. et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci. 2001;21(21):8370–7. [PubMed: 11606625]
7.
Ryu E.K. et al. Curcumin and dehydrozingerone derivatives: synthesis, radiolabeling, and evaluation for beta-amyloid plaque imaging. J Med Chem. 2006;49(20):6111–9. [PubMed: 17004725]
8.
Newberg A.B. et al. 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]

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