ABSTRACT
BACKGROUND: In-vivo imaging of dopamine transporter (DAT), a reliable marker of degeneration of nigrostriatal dopaminergic innervation, has gained increasing interest in preclinical neurodegenerative research for studying disease mechanisms and testing new therapeutic strategies. We assessed the feasibility and the reliability of in vivo and ex vivo quantification of Methyl (3S,4S,5R)-8-(3-fluoropropyl)-3-(4-iodophenyl)-8-azabicyclo[3.2.1]octane-4-carboxylate ([123I]FP-CIT) binding to striatal DAT sites in mouse brain. METHODS: Dedicated small animal single-photon emission computed tomography (SPECT) images of [123I]FP-CIT binding were obtained in 3 groups of healthy mice: untreated (N.=6), pre-treated with lugol solution (N.=4), and pre-treated with selective dopamine transporter uptake inhibitor GBR12909 (N.=4). Ex-vivo autoradiography studies were performed at the end of SPECT studies with phosphor image system in 4 out of the 6 untreated mice and in all mice pre-treated with lugol. Regions of interest were defined over the striatum. The specific binding (SB) was calculated using the cerebral cortex as reference region. RESULTS: SPECT images in untreated mice showed high [123I]FP-CIT uptake in the striatum and extracerebral regions. Lugol pretreatment improved striatal images quality decreasing salivary and thyroid glands uptake. SB was higher (P<0.0001) in mice pre-treated with lugol (5.97±0.60) than in untreated mice (2.25±0.28). Autoradiography showed similar SB findings in untreated (2.27±0.33) and lugol-treated (4.27±0.57) mice (P<0.0001). In-vivo striatal 123I-FP-CIT SB and ex-vivo striatal 123I-FP-CIT SB were significantly correlated (r=0.87; P<0.0001). SPECT competition studies showed a significant (P<0.0001) reduction of [123I]FP-CIT SB in the striatum after GBR12909. CONCLUSIONS: We demonstrated the feasibility of [123I]FP-CIT imaging of the normal mouse brain using small-animal SPECT without pinhole collimators. The reliability of quantitative measurement of striatal [123I]FP-CIT SB is supported by competition studies showing measurable inhibition of uptake induced by GBR12909 and by the strong correlation between in vivo and ex vivo striatal [123I]FP-CIT SB. Our data also demonstrate that pre-treatment with lugol might improve striatal [123I]FP-CIT SB in mice.
Subject(s)
Dopamine Plasma Membrane Transport Proteins/metabolism , Neostriatum/diagnostic imaging , Neostriatum/metabolism , Tomography, Emission-Computed, Single-Photon/methods , Tropanes/metabolism , Animals , Biological Transport , Dopamine/metabolism , Feasibility Studies , Mice , Protein Binding , Reproducibility of ResultsABSTRACT
Neuroinflammation (NI) is an adaptive response to different noxious stimuli, involving microglia, astrocytes and peripheral immune cells. NI is a hallmark of several acute and chronic diseases of central nervous system (CNS) and contributes to both damage and repair of CNS tissue. Interventional or genetically modified rodent models mimicking human neuropathologies may provide valuable insights on basic mechanisms of NI, but also for improving the development of new diagnostic and therapeutic strategies. Preclinical positron emission tomography (PET) allows to investigate noninvasively the inflammatory response in CNS of rodent models at a molecular level, validating innovative probes for early diagnosis, and characterizing the time course of neuroinflammatory changes and their relationship with disease progression, as well as the effects of experimental treatments with high translational potential. In particular, recent efforts of preclinical PET field are intended to develop specific and selective radiotracers that target the activation of innate immune system in CNS. Here, we have reviewed the state of art for PET in relevant rodent models of acute and chronic neuropathologies associated with NI, with particular regard on imaging of activated microglia and astrocytes.