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Titolo:
SPECIFICITY OF DIASTEREOMERS OF [TC-99M]TRODAT-1 AS DOPAMINE TRANSPORTER IMAGING AGENTS
Autore:
MEEGALLA SK; PLOSSL K; KUNG MP; STEVENSON DA; MU M; KUSHNER S; LIABLESANDS LM; REINGOLD AL; KUNG HF;
Indirizzi:
UNIV PENN,DEPT RADIOL,3700 MARKET ST,ROOM 305 PHILADELPHIA PA 19104 UNIV PENN,DEPT RADIOL PHILADELPHIA PA 19104 UNIV PENN,DEPT PHARMACOL PHILADELPHIA PA 19104 UNIV DELAWARE,DEPT CHEM NEWARK DE 19716
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 4, volume: 41, anno: 1998,
pagine: 428 - 436
SICI:
0022-2623(1998)41:4<428:SODO[A>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
POSITRON EMISSION TOMOGRAPHY; MUSCARINIC ACETYLCHOLINE-RECEPTOR; BETA-CIT; BABOON BRAIN; STRUCTURAL CHARACTERIZATION; OXOMETAL COMPLEXES; PARKINSONS-DISEASE; STEROID-HORMONES; BINDING-AFFINITY; POSSIBLE LIGANDS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
64
Recensione:
Indirizzi per estratti:
Citazione:
S.K. Meegalla et al., "SPECIFICITY OF DIASTEREOMERS OF [TC-99M]TRODAT-1 AS DOPAMINE TRANSPORTER IMAGING AGENTS", Journal of medicinal chemistry, 41(4), 1998, pp. 428-436

Abstract

Recently, we reported the first human study of [Tc-99m]TRODAT-1, technetium, hyl]amino]-ethanethiolato(3-)-oxo-[1R-(exo-exo)]-, as an imaging agent of central nervous system (CNS) dopamine transporters. Due tothe existence of several chiral centers on this molecule, upon the formation of[Tc-99m]TRODAT-1 complex (2) several diastereomers could be created. Two major diastereomers of [Tc-99m]TRODAT-1 (2), designated as peak A (2A) and peak B (2B), were separated by HPLC. Biodistributionof the purified diastereomers ZA,B was evaluated in rats. It appears that 2A displayed a higher lipophilicity than 2B (PC = 305 and 229, respectively), and a similar trend was observed for the initial brain uptake at 2 min postinjection (0.50% and 0.28% dose/organ for 2A,B, respectively). At 60 min post-iv-injection, the specific uptakes, as measured by [striatum - cerebellum]/cerebellum ([ST-CB]ICB) ratio, were 1.72 and 2.79 for 2A,B, respectively. The higher [ST-CB]/CB ratio observed for 2B was corroborated by the results of an in vitro binding assay. Higher binding affinity for dopamine transporters was observed for 3B(K-i = 13.87 and 8.42 nM for the analogous rhenium complexes 3A,B, respectively). The structure of the [Tc-99m]TRODAT-1 complexes was deduced using nonradioactive rhenium as a surrogate for radioactive technetium complex. Reacting free TRODAT-1 ligand with [Bu4N][ReOCl4] yieldedtwo major complexes: Re-TRODAT-1A (3A) and Re-TRODAT-1B (3B) (corresponding with peaks A and B of[Tc-99m]TRODAT-1, respectively), whose structures were determined by X-ray analysis. The X-ray structures show that both complexes have a pseudo-square-pyramidal structure of [(ReO)-O-v]3+N2S2 core with oxygen occupying the apical position and the N-alkyl substitution in syn-configuration to the oxo-rhenium bond. In conclusion, TRODAT-1 formed at least two diastereomers after complexing with a metal(V)-oxo (M = (99)mTc, Re) center core. The two isomers display different binding affinities toward dopamine transporters and distinct properties of localization in the striatum area of the brain wherethe transporters are located.

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Documento generato il 25/01/20 alle ore 06:53:54