Background

[PubMed]

Alzheimer’s disease (AD) is a major neurodegenerative disease associated with an irreversible decline of mental functions and with cognitive impairment (1, 2). It is characterized by the presence, in the brain, of senile plaques of β-amyloid (Aβ) peptides with intracellular neurofibrillary tangles of filaments containing the hyperphosphorylated protein tau (3, 4). Accelerated deposition of Aβ deposits seems to be a key risk factor associated with AD, and although the mechanisms of the disease are still not fully understood, reducing the deposition of amyloid plaques seems to benefit patients.

Several radioligands for positron emission tomography (PET) have been developed (5-7) and tested in humans as in vivo diagnostic tools for imaging and measuring the formation and Aβ deposits (7). The first successful agent used in human studies was 2-(1-(6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ([¹⁸F]FDDNP) (8), a malonitrile derivative found to bind to both neurofibrillary tangles and Aβ plaques. The second successful attempt in humans was made with [¹¹C]PIB (9), also known as Pittsburgh Compound B or [¹¹C]6-OH-BTA-1. [¹¹C]PIB showed marked retention in areas of association cortex known to contain substantial amounts of Aβ deposits. The third PET radioligand tested in humans was [¹¹C]4-N-methylamino-4´-hydroxystilbene, a stilbene derivative commonly named [¹¹C]SB-13. SB-13 was also synthesized and labeled with either I-123 or C-11 for in vivo imaging using PET.

The radioiodinated ligand 6-iodo-2-(4´-dimethylamino)-phenyl-imidazo[1,2-a]pyridine ([¹²⁵I]IMPY or [¹²³I]IMPY), is a novel probe displaying high specific binding for Aβ plaques and very favorable brain uptake kinetics in rodents. Published research has shown that this radioligand was a good candidate for the detection of Aβ plaques in humans when used with single-photon emission computed tomography (SPECT).

Synthesis

[PubMed]

[¹²⁵I]IMPY or [¹²³I]IMPY can be prepared by an iododestannylation reaction from the corresponding tin precursor using hydrogen peroxide as catalyst. Using this protocol, Kung et al. (10) obtained the no-carrier-added product with a high specific activity (81,400 GBq/mmol (2,200 Ci/mmol) for [¹²⁵I]IMPY and 8,140 GBq/mol (220,000 Ci/mmol) for [¹²³I]IMPY), an overall yield ranging from 30 to 45%, and a radiochemical purity greater than 95%. The method reported by the authors (10) in 2002 used a purification process that included high-pressure liquid chromatography (HPLC). The stabilities of the purified tracers (by HPLC) were 6 h at room temperature for [¹²³I]IMPY and 8 weeks for [¹²⁵I]IMPY stored in 100% ethanol at –20°C.

A simplified method was reported by Kung et al. (11) in 2004. This method improved the yield and simplified the purification process of the radioiodinated IMPY. Purification was done with a simple C₄ mini-column with stepwise washing and elution using ethanol (3 ml at 10% and 3 ml at 20% for the washing). The radiochemical yield obtained was >50%, and the total synthesis time was less than 1 h. The radiochemical purity obtained was >95% (determined by HPLC or thin-layer chromatography).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro binding assays using preformed synthetic Aβ40 aggregates (10) showed that [¹²⁵I]IMPY had very good binding affinities for amyloid plaques while competing well for the thioflavin binding site recognized by [¹²⁵I]2-(4´-dimethylaminophenyl)-6-iodobenzothiazole ([¹²⁵I]TZDM), a selective probe for amyloid plaques studied previously (12). The inhibition coefficient (K_i) for [¹²⁵I]IMPY was 15 ± 5 nM (at 25 °C). Replacement of the iodine by a methyl or hydrogen appeared to substantially decrease the binding affinity of [¹²⁵I]IMPY for Aβ aggregates (K_i ~242 and 1242 nM for methyl group and hydrogen, respectively).

In vitro audiography of amyloid plaques in postmortem brain sections of AD patients showed distinct labeling of the plaques after exposure to [¹²⁵I]IMPY, whereas no specific binding of the tracer was observed in normal brains. The specificity of Aβ plaque labeling by [¹²⁵I]IMPY was further supported by blocking experiments using a competing concentration of thioflavin-T (100 µM). In addition, when pretreated with formic acid (which destroys the ß-sheet structure), the AD brain sections showed no retention of [¹²⁵I]IMPY (10).

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

References

1.

Heininger K . A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events. Rev Neurosci, 11 Spec No: p. 213-328. 2000 [PubMed: 11065271]

2.

Forstl H , Kurz A . Clinical features of Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci. 1999;249(6):288–290. [PubMed: 10653284]

3.

Hardy J . The relationship between amyloid and tau. J Mol Neurosci. 2003;20(2):203–206. [PubMed: 12794314]

4.

Brandt R , Leschik J . Functional interactions of tau and their relevance for Alzheimer's disease. Curr Alzheimer Res. 2004;1(4):255–269. [PubMed: 15975055]

5.

Nordberg A . PET imaging of amyloid in Alzheimer's disease. Lancet Neurol. 2004;3(9):519–527. [PubMed: 15324720]

6.

Bacskai BJ , Hickey GA , Skoch J , Kajdasz ST , Wang Y , Huang GF , Mathis CA , Klunk WE , Hyman BT . Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A. 2003;100(21):12462–12467. [PMC free article: PMC218780] [PubMed: 14517353]

7.

Wu C , Pike VW , Wang Y . Amyloid imaging: from benchtop to bedside. Curr Top Dev Biol. 2005;70:171–213. [PubMed: 16338342]

8.

Shoghi-Jadid K , Small GW , Agdeppa ED , Kepe V , Ercoli LM , Siddarth P , Read S , Satyamurthy N , Petric A , Huang SC , Barrio JR . Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002;10(1):24–35. [PubMed: 11790632]

9.

Klunk WE , Engler H , Nordberg A , Wang Y , Blomqvist G , Holt DP , Bergstrom M , Savitcheva I , Huang GF , Estrada S , Ausen B , Debnath ML , Barletta J , Price JC , Sandell J , Lopresti BJ , Wall A , Koivisto P , Antoni G , Mathis CA , Langstrom B . Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306–319. [PubMed: 14991808]

10.

Kung MP , Hou C , Zhuang ZP , Zhang B , Skovronsky D , Trojanowski JQ , Lee VM , Kung HF . IMPY: an improved thioflavin-T derivative for in vivo labeling of beta-amyloid plaques. Brain Res. 2002;956(2):202–210. [PubMed: 12445687]

11.

Kung MP , Hou C , Zhuang ZP , Cross AJ , Maier DL , Kung HF . Characterization of IMPY as a potential imaging agent for beta-amyloid plaques in double transgenic PSAPP mice. Eur J Nucl Med Mol Imaging. 2004;31(8):1136–1145. [PubMed: 15007564]

12.

Zhuang ZP , Kung MP , Hou C , Skovronsky DM , Gur TL , Plossl K , Trojanowski JQ , Lee VM , Kung HF . Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates. J Med Chem. 2001;44(12):1905–1914. [PubMed: 11384236]

13.

Zhuang ZP , Kung MP , Wilson A , Lee CW , Plossl K , Hou C , Holtzman DM , Kung HF . Structure-activity relationship of imidazo[1,2-a]pyridines as ligands for detecting beta-amyloid plaques in the brain. J Med Chem. 2003;46(2):237–243. [PubMed: 12519062]