[18F]FMS-IMPY and [18F]FES-IMPY as potential radioligands for imaging brain beta-amyloid

Abstract

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Objectives: 11C- or 18F-labeled derivatives of IMPY can be potential agents for imaging beta-amyloid in Alzheimer’s disease with PET. We synthesized two new derivatives of IMPY, namely FMS-IMPY (4-(6-(fluoromethylthio)imidazo[1,2-a]pyridin-2-yl)-N,N-dimethylaniline) and FES-IMPY (4-(6-(2-fluoroethylthio)imidazo[1,2-a]pyridin-2-yl)-N,N-dimethylaniline) for measurement of binding affinity to beta-amyloid, and also labeled them with fluorine-18 to determine their pharmacokinetics and metabolism in normal rhesus monkeys. Methods: We synthesized a key thiol precursor through a multi-step reaction sequence. Treatment of this precursor under strongly basic conditions with [18F]fluoromethyl bromide or [18F]2-fluoroethyl bromide generated the respective [18F]FMS-IMPY [18F]FES-IMPY. Each purified radioligand was injected intravenously into normal monkey followed by sequential dynamic brain scanning for 120 min with an HRRT scanner to determine pharmacokinetics. The time-activity curves expressed in percent standardized uptake values (%SUV) were calculated from the acquired PET data. Results: Use of the phosphorane base was found critical for achieving high yield radiolabeling. FMS-IMPY and FES-IMPY were found to have high affinity (Ki < 10 nM) for AD brain homogenates in vitro. Decay-corrected radiochemical yields of formulated [18F]FMS-IMPY and [18F]FES-IMPY from cyclotron-produced [18F]fluoride ion were 4.9±2.4 (n = 5) and 6.9±4.9 (n = 9)%, respectively. The uptake of radioactivity into monkey brain after i.v. injection of [18F]FMS-IMPY was high (250−450% SUV at 2.2−4.5 min, n = 1) and greater than that of the currently established radioligand, [11C]PIB (200−290% SUV at 4−6 min; n = 1). The ratio of radioactivity at its maximum to that at 60 min was 2.9−4.8 (c.f. ~ 4.6 for [11C]PIB). When [18F]FES-IMPY was used in the PET imaging experiment, the uptake was 244−519% SUV at 2.2−4.5 min (n = 1) and the ratio of maximum radioactivity to that at 60 min was 2.3−3.8. [18F]FES-IMPY showed a lower degree of defluorination than [18F]FMS-IMPY. Conclusions: [18F]FMS-IMPY and [18F]FES-IMPY show promising affinities and kinetics for imaging beta-amyloid in vivo and are under further evaluation.