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Titolo:
Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates
Autore:
Zhuang, ZP; Kung, MP; Hou, C; Skovronsky, DM; Gur, TL; Plossl, K; Trojanowski, JQ; Lee, VMY; Kung, HF;
Indirizzi:
Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA Univ Penn PhiladelphiaPA USA 19104 pt Radiol, Philadelphia, PA 19104 USA Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 & Lab Med, Philadelphia, PA 19104 USA Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA Univ Penn Philadelphia PA USA 19104 Pharmacol, Philadelphia, PA 19104 USA
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 12, volume: 44, anno: 2001,
pagine: 1905 - 1914
SICI:
0022-2623(20010607)44:12<1905:RSATAP>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
PHOTON EMISSION TOMOGRAPHY; ALZHEIMERS GAMMA-SECRETASE; CONGO-RED; FIBRIL FORMATION; BETA-PEPTIDE; CHRYSAMINE-G; DISEASE BRAIN; DOWN-SYNDROME; IN-VIVO; BINDING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Kung, HF Univ Penn, Dept Radiol, Room 305,3700 Market St, Philadelphia, PA19104 USA Univ Penn Room 305,3700 Market St Philadelphia PA USA 19104 4 USA
Citazione:
Z.P. Zhuang et al., "Radioiodinated styrylbenzenes and thioflavins as probes for amyloid aggregates", J MED CHEM, 44(12), 2001, pp. 1905-1914

Abstract

We report for the first time that small molecule-based radiodiodinated ligands, showing selective binding to A beta aggregates, cross the intact blood-brain barrier by simple diffusion. Four novel ligands showing preferential labeling of amyloid aggregates of A beta (1-40) and A beta (1-42) peptides, commonly associated with plaques in the brain of people with Alzheimer'sdisease (AD), were developed. Two I-125-labeled styrylbenzenes, (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-hydroxy)-styrylbenzene, 12 (ISB), and (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-methoxy)styrylbenzene, 13 (IMSB), and two I-125-labeled thioflavins, 2-[4 '-(dimethylamino)phenyl]-6-iodobenzothiazole, 18a (TZDM), and 2- [4 '-(4 " -methylpiperazin-1-yl)phenyl]-6-iodobenzothiazole, 18b (TZPI), were prepared at a high specific activity (2200 Ci/mmol). In vitro binding studies of these ligands showed excellent binding affinities with K-d values of 0.08, 0.13, 0.06, and 0.13 nM for aggregates of A beta (1-40) and 0.15, 0.73, 0.14, and 0.15 nM for aggregates of A beta (1-42), respectively. Interestingly, under a competitive-binding assaying condition, different binding sites on A beta (1-40) and A beta (1-42) aggregates, which are mutually exclusive, were observed for styrylbenzenes and thioflavins. Autoradiography studies of postmortem brain sections of a patient with Down's syndrome known to contain primarily A beta (1-42) aggregates inthe brain showed that both [I-125]18a and [I-125]18b labeled these brain sections, but [I-125]13, selective for A beta (1-40) aggregates, exhibited very low labeling of the comparable brain section. Biodistribution studies in normal mice after an iv injection showed that [I-125]18a and [I-125]18b exhibited excellent brain uptake and retention, the levels of which were much higher than those of [I-125]12 and [I-125]13. These findings strongly suggest that the new radioiodinated ligands, [I-125]12 (ISB), [I-125]13 (IMSB), [I-125]18a, (TZDM), and [I-125]18b (TZPI), may be useful as biomarkers for studying A beta (1-40) as well as A beta (1-42) aggregates of amyloidogenesis in AD patients.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 03:23:40