METAL OXIDES NANOPARTICLES CONJUGATED WITH NAPHTHALENE DERIVATIVES AS CONTRAST AGENTS FOR THE DETECTION OF BETA AMYLOID PLAQUES BY MAGNETIC RESONANCE IMAGES

摘要

This invention is related to Chemistry and Physics applied to the field of Medicine and refers to the use of compounds with magnetic properties, which belong to the category of metal oxide nanoparticles, coated and conveniently functionalized, which are conjugated with naphthalene compounds related to agglomerates and β-amyloid plaques present in neurodegenerative diseases. These new nanoparticles (NPs) are used for the non-invasive detection of agglomerates and amyloid plaques using the Magnetic Resonance Imaging (MRI) technique. The nanoparticles described here cross the blood-brain barrier (BBB), without the use of any membrane-disrupting agent. Likewise, they bind with high affinity and specificity to the agglomerates and β-amytoid plaques, and are used as contrast agents in MRI for the early detection of Alzheimer's disease (AD).;The new nanoparticles, coated, functionalized and conjugated with the naphthalene derivatives, have general Formula I;wherein:R1: is an organic coating to the metal oxide core, of polymeric type, catechol derivatives and trialkoxyalkylaminosilane;R2: -NHCO-alkylenyl-C(O)NH-alkylenyl-R3;R3: -COO-, -CO-, -NH, -O-, -S-, -NH-alkylenyl-NH-, -NR4-CSS-;R4: -H, -CH3, -CH2-CH3, -CH2CH2CH3, andMxOy: iron oxide (Fe3O4/γFe2O3), gadolinium oxide(III), manganese oxide(II) and copper(II) oxide;wherein the conjugated, functionalized and coated magnetic nanoparticle is capable of, when it is administered to a mammal, crossing the blood-brain barrier and specifically binding to the agglomerates and amyloid plaques present in brain tissue;wherein with this nanoparticle bound to the agglomerates and β-amyloid plaques in the brain tissue, hypo- or hyper-intense signals are observed in the region of interest through MRI.;The compounds of Formula I are capable of acting as positive (T1) and / or negative (T2) contrast agents for MRI for the early and non-invasive diagnosis of AD, through a hypo- or hyper-intense signal of the β-amytoid agglomerates or Aβ plaques.;In the NPs of Formula I, the metallic oxide magnetic core is coated with a functionalized polymeric layer that allows conjugation to naphthalene compounds, the preparation of which has been previously described in CU 2010/0204, EP 2 436 666 A20, P58243ZA00, US 9,764,047, CA 2789869C, PI 2012003534.;The covalent and stable bond between the two chemical units form, in the NPs, a carbon chain with a singular structure, which surprisingly facilitates the NPs passage through the BBB, without the use of a disrupting agent, what are not described in the current state-of-the-art.;These NPs unexpectedly enhance the affinity and selectivity properties of the naphthalene derivatives towards the Aβ agglomerates and β-plaques, they are stable molecules and do not show toxicity. We are not aware that the compounds presented in this invention have been previously reported.