Synthesis and evaluation of two fluorine‐18 labelled phenylbenzothiazoles as potential in vivo tracers for amyloid plaque imaging

Abstract

AbstractUncharged derivatives of thioflavin‐T have known in vitro and in vivo affinity for amyloid β. We synthesized and evaluated two derivatives with a fluorine‐18 labelled fluoropropoxy substituent either at the 6‐position or at the 2′‐position of the 2‐(4′‐aminophenyl)‐1,3‐benzothiazole core with the aim to get suitable radiotracers to perform amyloid plaque imaging. The fluorine‐18 labelled compounds were obtained by nucleophilic substitution of the corresponding tosyl precursors with [18F]fluoride with a radiochemical yield of 50%, yielding 6‐(3′′‐[18F]fluoropropoxy)‐2‐(4′‐aminophenyl)‐1,3‐benzothiazole ([18F]2) and 2‐[2′‐(3′′‐[18F]fluoropropoxy)‐4′‐aminophenyl]‐1,3‐benzothiazole ([18F]3) with a specific activity between 33 and 51 GBq/µmol. The identity of the radiolabelled compounds was confirmed using radio‐LC‐MS and by comparing retention times on RP‐HPLC. Biodistribution studies in healthy mice showed for both compounds a relatively high initial brain uptake, which was significantly higher for [18F]2 than for [18F]3 (4.5% ID/g versus 3.0% ID/g, p<0.05). Wash‐out from control brain was faster for [18F]3. In vitro binding affinity tests using human AD brain homogenates revealed that only compound 2 has affinity for fibrillar amyloid β (Ki=14.5 nM). This was confirmed by the incubation of transgenic APP mouse brain sections with the cold compounds, where 3 did not stain any structure whereas 2 stained amyloid plaques present in APP mouse brain. These data suggest that [18F]2 may be a useful tracer for in vivo visualization of fibrillar amyloid β. Copyright © 2009 John Wiley & Sons, Ltd.