2-(4--(methylamino)phenyl)-6-hydroxybenzothiazole and Demyelinating-Diseases

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [

Topics: Aniline Compounds; Animals; Autoradiography; Brain Edema; Carbon Radioisotopes; Cerebral Ventricles; Corpus Callosum; Corpus Striatum; Demyelinating Diseases; Dilatation, Pathologic; Disease Models, Animal; Ethylene Glycols; False Positive Reactions; Fluorine Radioisotopes; Image Processing, Computer-Assisted; Injections; Lysophosphatidylcholines; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Myelin Sheath; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques; Thiazoles

Imaging of myelin tracts in vivo would greatly improve the monitoring of demyelinating diseases such as multiple sclerosis (MS). To date, no imaging technique specifically targets demyelination and remyelination. Recently, amyloid markers related to Congo red have been shown to bind to central nervous system (CNS) myelin. Here we questioned whether the thioflavine-T derivative 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also binds to amyloid plaques, could serve as a myelin marker.. PIB fixation to myelin was studied by fluorescence in the normal and dysmyelinating mouse brain, as well as in the postmortem brain of MS patients. Positron emission tomography (PET) experiments were conducted using [¹¹C]PIB in baboons and in a proof of concept clinical study in 2 MS patients.. Applied directly on tissue sections or after intraperitoneal injection, PIB stained CNS myelin, and the decrease in the level of fixation paralleled the amount of myelin loss in a dysmyelinating mutant. In normally myelinated areas of postmortem MS brain, demyelinated and remyelinated lesions were clearly distinguishable by the differential intensity of labeling observed with PIB. PET using intravenously injected radiolabeled [¹¹C]PIB imaged CNS myelin in baboons and humans. In MS patients, the dynamic analysis of PET acquisitions allowed quantitative assessment of demyelination.. PIB could be used as an imaging marker to quantify myelin loss and repair in demyelinating diseases.

Topics: Aniline Compounds; Animals; Benzothiazoles; Brain; Cadaver; Carbon Radioisotopes; Demyelinating Diseases; Humans; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Multiple Sclerosis; Nerve Regeneration; Papio anubis; Positron-Emission Tomography; Thiazoles