US 12,311,036 B2
Metal oxides nanoparticles conjugated with naphthalene derivatives as contrast agents for the detection of beta amyloid plaques by magnetic resonance images
Chryslaine Rodriguez-Tanty, Havana (CU); Marquiza Sablón Carrazana, Havana (CU); Evelio González Dalmau, Havana (CU); Alicia Marcelina Díaz García, Havana (CU); Armando Augusto Paneque Quevedo, Havana (CU); Andy Guzmán Rodríguez, Havana (CU); Julio Ricardo Rodríguez Izquierdo, Havana (CU); Suchitil Rivera Marrero, Havana (CU); Armando José Hernández Rodríguez, Artemisa (CU); Israel Reyes Molina, Havana (CU); Claudia Iriarte Mesa, Havana (CU); Samila León Chaviano, Havana (CU); Roberto Soto Menéndez Del Valle, Havana (CU); and Alberto Bencomo Martínez, Artemisa (CU)
Assigned to Centro De Neurociencias De Cuba, Havana (CU); and Facultad De Quimica Universidad De La Habana, Havana (CU)
Appl. No. 17/291,996
Filed by CENTRO DE NEUROCIENCIAS DE CUBA, Havana (CU); and FACULTAD DE QUÍMICA UNIVERSIDAD DE LA HABANA, Havana (CU)
PCT Filed May 13, 2019, PCT No. PCT/CU2019/050005
§ 371(c)(1), (2) Date May 6, 2021,
PCT Pub. No. WO2020/094161, PCT Pub. Date May 14, 2020.
Claims priority of application No. 2018-0138 (CU), filed on Nov. 6, 2018.
Prior Publication US 2021/0290782 A1, Sep. 23, 2021
Int. Cl. A61K 49/18 (2006.01); B82Y 5/00 (2011.01); B82Y 30/00 (2011.01); B82Y 40/00 (2011.01)
CPC A61K 49/186 (2013.01) [B82Y 5/00 (2013.01); B82Y 30/00 (2013.01); B82Y 40/00 (2013.01)] 4 Claims
 
1. A magnetic nanoparticle related to the agglomerates and β-amyloid plaques for the diagnosis of Alzheimer's disease by magnetic resonance imaging, characterized by compounds of Formula I comprising a metal oxide core coated with a multifunctional organic layer, wherein said organic layer is conjugated with a naphthyl compound,

OG Complex Work Unit Chemistry
wherein:
R1: is an organic coating to the metal oxide core, of polymeric type selected from the group polyethylene glycol (PEG), amino-PEG, PEG-carboxyl acid, amino-PEG-carboxyl acid, PEG-di carboxyl acid, PEG-polylactic acid, and PEG-polylactic-co-glycolic acid;
R2: is —NHCO-alkylenyl-C(O)NH-alkylenyl-R3;
R3: is —COO—, —CO—, —NH, —O—, —S—, —NH-alkylenyl-NH—, —NR4—CSS—;
R4: is —H, —CH3, —CH2—CH3, —CH2CH2CH3, and
MxOy: is iron oxide (Fe3O4/γFe2O3), gadolinium oxide(III), manganese oxide(II) or copper(II) oxide;
wherein the naphthyl compound is selected from the group: N1-(2-aminoethyl)-N4-(1-naphthyl)succinamide, N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine, 6-{[4-(1-naphthylamino)-4-oxobutanoyl]amino}hexanoic acid, N1-(2-aminobutyl)-N4-(1-naphthyl)succinamide, N-(2-hydroxyethyl)-N′-1-naphthyl succinamide, N-(3-mercaptopropyl)-N′-1-naphthysuccinamide, N-{2-[(2-aminoethyl)amino]ethyl}-N′-1-naphthysuccinamide and (2-{[4-(1-naphthylamino)-4-oxobutanoyl]amino}ethyl)carbamodithioic acid sodium salt;
wherein the alkylenyl term in R2 and R3 is selected from the group consisting of ethylenyl (—CH2CH2—), butylenyl (—CH2CH2CH2CH2—) and hexylenyl (—CH2CH2CH2CH2CH2CH2—);
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 β-amyloid plaques present in brain tissue;
wherein, with the 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 magnetic resonance imaging.