Synthesis and evaluation of two uncharged 99mTc‐labeled derivatives of thioflavin‐T as potential tracer agents for fibrillar brain amyloid

Thioflavin‐T is a fluorescent dye for in vitro detection of fibrillar amyloid β, a protein found in the brain of patients suffering from Alzheimer's disease. We synthesized and biologically evaluated two uncharged ^99mTc‐labeled derivatives of thioflavin‐T. The precursors for labeling were synthesized by coupling an S,S′‐bis‐triphenylmethyl‐N‐tert‐butoxycarbonyl bis‐amino‐bis‐thiol tetradentate ligand via a propoxy spacer to 2‐(4′‐aminophenyl)‐1,3‐benzothiazole at the 6‐position or the 2′‐position. Deprotection and labeling with ^99mTc were done via a one‐pot procedure (15% yield) after which the labeled compound was isolated by high performance liquid chromatography (LC). LC in combination with mass spectrometry (MS) was used for identity confirmation of the labeled compounds. Results of electrophoresis and log P determination supported the assumption that the radiolabeled compounds could cross the blood–brain barrier by passive diffusion. However, in normal mice both compounds showed a low brain uptake 2 min post injection. They were mainly excreted through the hepatobiliary system, with some accumulation in the stomach. Sixty minutes after intravenous injection, 37% of the ^99mTc‐activity in the blood corresponded to the original compound. In view of the low brain uptake, it is concluded that the studied ^99mTc‐labeled derivatives of thioflavin‐T are not suitable as tracer agents for in vivo visualization of amyloid in brain. Copyright © 2009 John Wiley & Sons, Ltd.