Deposition of beta-amyloid (Abeta) plaques in the brain is likely linked to the pathogenesis of Alzheimer's disease (AD). Developing specific Abeta aggregate-binding ligands as in vivo imaging agents may be useful for diagnosis and monitoring the progression of AD. We have prepared a thioflavin derivative, 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2-a]pyridine, IMPY, which is readily radiolabeled with 125I/123I for binding or single-photon emission computerized tomography (SPECT) imaging studies. Characterization of [125I]IMPY binding to plaque-like structures was evaluated in double transgenic PSAPP mice. [125I]IMPY labeled Abeta plaques in transgenic mouse brain sections, and the labeling was consistent with fluorescent staining and Abeta-specific antibody labeling. Significant amounts of Abeta plaques present in the cortical, hippocampal, and entorhinal regions of the transgenic mouse brain were clearly detected with [125I]IMPY via ex vivo autoradiography. In contrast, [125I]IMPY showed little labeling in the age-matched control mouse brain. Tissue homogenate binding further corroborated the Abeta plaque-specific distribution in various brain regions of transgenic mouse, and correlated well with the known density of Abeta deposition. Using a tissue dissection technique, [125I]IMPY showed a moderate increase in the cortical region of transgenic mice as compared to the age-matched controls. In vitro blocking of [125I]IMPY by "carrier" observed via autoradiography in mouse brain sections was not replicated by an in vivo blocking experiment in living TT mouse brain. The failure was most likely due to a significant carrier effect, which slows down the tracer in vivo metabolism, leading to an increased brain uptake. Taken together, these data indicate that [123I]IMPY is a potentially useful SPECT imaging agent for in vivo labeling of Abeta plaques in the living brain.