PT - JOURNAL ARTICLE AU - Damian Brockschnieder AU - Heribert Schmitt-Willich AU - Tobias Heinrich AU - Andrea Varrone AU - Balázs Gulyás AU - Miklos Toth AU - Jan Andersson AU - Ulf Boemer AU - Sabine Krause AU - Matthias Friebe AU - Ludger Dinkelborg AU - Christer Halldin AU - Thomas Dyrks TI - Preclinical Characterization of a Novel Class of <sup>18</sup>F-Labeled PET Tracers for Amyloid-β AID - 10.2967/jnumed.112.104810 DP - 2012 Nov 01 TA - Journal of Nuclear Medicine PG - 1794--1801 VI - 53 IP - 11 4099 - http://jnm.snmjournals.org/content/53/11/1794.short 4100 - http://jnm.snmjournals.org/content/53/11/1794.full SO - J Nucl Med2012 Nov 01; 53 AB - Imaging of amyloid-β (Aβ) plaques by PET is more and more integrated into concepts for Alzheimer disease (AD) diagnosis and drug development. The objective of this study was to find novel chemical entities that can be transformed into 18F-labeled Aβ tracers with favorable brain washout kinetics and low background signal. Methods: High-throughput screening of a large chemical library was used to identify new ligands for fibrillar aggregates of Aβ1–42 peptide. Thirty-two fluorinated derivatives were synthesized and tested for their affinity toward AD brain homogenate. Twelve ligands have been radiolabeled with 18F. The pharmacokinetic properties of the radioligands were investigated in mouse and monkey biodistribution studies. Binding characteristics were determined by autoradiography of AD brain sections in vitro and using amyloid precursor protein transgenic mice in vivo. Results: The systematic search for Aβ imaging agents revealed several fluorinated derivatives with nanomolar affinity for Aβ. The fluoropyridyl derivative BAY 1008472 showed a high initial brain uptake (6.45 percentage injected dose per gram at 2 min) and rapid brain washout (ratio of percentage of injected dose per gram of tissue at 2 and 30 min after injection, 9.2) in mice. PET studies of healthy rhesus monkeys confirmed the high initial brain uptake of BAY 1008472 (2.52 standardized uptake value at peak) and a fast elimination of total radioactivity from gray and white matter areas (ratio of standardized uptake value at peak uptake and 60 min 11.0). In autoradiographic analysis, BAY 1008472 selectively detected Aβ deposits in human AD brain sections with high contrast and did not bind to τ- or α-synuclein pathologies. Finally, ex vivo autoradiography of brain sections from amyloid precursor protein-transgenic mice confirmed that BAY 1008472 is indeed suitable for the in vivo detection of Aβ plaques. Conclusion: A new chemical class of Aβ tracers has been identified by high-throughput screening. The fluoropyridyl derivative BAY 1008472 shows a favorable preclinical profile including low background binding in gray and white matter. These properties might qualify this new tracer, in particular, to detect subtle amounts or changes of Aβ burden in presymptomatic AD and during therapy.