[S-methyl-¹¹C]N,N-Dimethyl-4-(6-(methylthio)imidazo[1,2-a]pyridine-2-yl)aniline

Background

[PubMed]

Alzheimer’s disease (AD) is a major neurodegenerative disease associated with an irreversible decline of mental functions and with cognitive impairment (1). It is characterized pathologically by neuronal loss with the presence in the brain of senile plaques of β-amyloid (Aβ) peptides and intracellular neurofibrillary tangles of filaments that contain the hyperphosphorylated protein tau (2, 3). Accelerated deposition of Aβ deposits seems to be a key risk factor associated with AD.

Early diagnosis of AD is important for treatment consideration and disease management (4). Several radioligands [PubMed] 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 of Aβ deposits (7). The first agent successfully used in human studies was [¹⁸F]FDDNP (8), a malonitrile derivative found to bind to both neurofibrillary tangles and Aβ plaques. The second successful agent was [¹¹C]PIB (9), also known as Pittsburgh Compound B or [¹¹C]6-OH-BTA-1, which showed marked retention in areas of the cortex known to contain substantial amounts of Aβ deposits. The third PET radioligand successfully tested in humans was [¹¹C]4-N-methylamino-4’-hydroxystilbene ([¹¹C]SB-13), a stilbene derivative that exhibits good binding affinities for Aβ aggregates in vitro, moderate lipophilicity, high initial brain uptake in the normal rat cortex, and a rapid washout (10).

[¹²⁵I]6-Iodo-2-(4’-dimethylamino)-phenyl-imidazo[1,2-a]pyridine ([¹²⁵I]IMPY) displays a high specific binding for Aβ plaques and favorable brain uptake kinetics in rodents for single-photon emission computed tomography (SPECT). [S-methyl-¹¹C]N,N-Dimethyl-4-(6-(methylthio)imidazo[1,2-a]pyridine-2-yl)aniline ([¹¹C]MeS-IMPY) has been synthesized as an S-methyl analog of [¹²⁵I]IMPY and is currently being studied as a PET radioligand for Aβ plaques (11).

Synthesis

[PubMed]

[¹¹C]MeS-IMPY was synthesized from its precursor by S-methylation in acetonitrile with the use of ¹¹C-methyl iodide (80°C for 5 min) (11). [¹¹C]MeS-IMPY was purified by reversed-phase high-performance liquid chromatography with >98% radiochemical purity. The radiochemical yields (decay-corrected) on the basis of [¹¹C]CO₂ were 10–15% , and the specific activities were 37–148 GBq/µmol (1.0–4.0 Ci/µmol) at the end of synthesis.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

MeS-IMPY was found to have an inhibition constant (K_i) value of 7.93 nM using human AD brain homogenates (11). MeS-IMPY exhibited a moderate lipophilicity (log D value of 4.1 at pH 7.4). These values are comparable to those of IMPY (K_i value of 8.95 nM and log D value of 3.58).

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

NIH Support

Intramural Research Program

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