Bioorg. Med. Chem. 29 (2021) 115884 Available online 23 November 2020 0968-0896/© 2020 Elsevier Ltd. All rights reserved. 18 F-labeled 2-phenylbenzoheterocycles with chiral dihydroxyl side chains as β-amyloid imaging probes Yuying Li, Kaixiang Zhou, Wentao Guo, Mengchao Cui * Key Laboratory of Radiopharmaceuticals, Ministry of Education, Beijing Normal University, Beijing 100875, China A R T I C L E INFO Keywords: Alzheimer’s disease Aβ plaques 2-Phenylbenzoheterocycles PET imaging Pharmacokinetic ABSTRACT This study reported the design, synthesis and bio-evaluation of 2-phenylbenzoheterocycles with chiral dihy- droxyl side chains as β-amyloid (Aβ) imaging probes. This strategy of introducing two hydroxyls offered a simplifed method for effectively reducing the lipophilicity. The probes (R, S)/(S, R)-14–15 with benzothiazole scaffold displayed good binding affnities toward Aβ 1-42 aggregates with K i values ranging from 47.63 to 56.28 nM. Further biological studies shown that (R, S)/(S, R)-[ 18 F]14 have no obvious chirality-related discrepancy in binding ability and mice bio-distribution, while (S, R)-enantiomer exhibited slightly faster brain washout rate than (R, S)-enantiomer. Compared to the FDA approved [ 18 F]Florbetapir and the fuoro-peglated 2-phenylben- zothiazole derivatives, (S, R)-[ 18 F]14 displayed improved brain kinetics (6.40% ID/g at 2 min, brain 2 min / brain 60 min = 7.80) that is favorable for further application. In vitro autoradiography studies validated its high affnity and specifcity to Aβ plaques. Overall, (S, R)-[ 18 F]14 deserved further detailed study as a potential PET imaging probe for AD early diagnosis. 1. Introduction Alzheimer’s disease (AD) is a complex neurodegenerative disease that seriously threatens the health of the elderly, bringing a heavy economic and psychological burden to the patients’ families and soci- ety 1,2 . In the past 100 years, researchers have found and confrmed that the extracellular β-amyloid (Aβ) plaques, intracellular neurofbrillary tangles (NFTs) and neuroinfammation are the main pathogenic factors of AD 3 . In 2018, through a large number of clinical and pathological studies, the workgroup of National Institute on Aging and Alzheimer’s Association (NIA-AA) updated and concluded a new research frame- work, pointing out Aβ deposition (A), abnormal tau (T), and neuro- degeneration (N) are major characters for the classifcation and staging of preclinical AD 4, 5 . Notably, Aβ is a specifc biomarker for identifying individual in Alzheimer’s categories, known as Alzheimer’s continuum. In addition, previous studies have shown that abnormal changes of Aβ occur 10–20 years earlier than clinical symptoms, and accumulate along with the development of AD 6–7 . Thus, using positron emission tomog- raphy (PET) imaging, a noninvasive technique, will enable doctors to detect the level of Aβ plaques in the brain and achieve early diagnosis 8, 9 . Over the previous decades, numerous compounds derivates from Congo red (CR) and Thiofavin-T (Th-T) scaffolds were offered as the Aβ- specifc neuroimaging radiotracers. The Th-T analog, 11 C-labeled Pitts- burgh compound B ([ 11 C]PiB) was an agent extensively studied in humans. Unfortunately, the short half-life of 11 C (t 1/2 = 20.4 min) limited its clinical application 10 . To overcome this defciency, fuori- nated version of PiB, [ 18 F]Flutemetamol was approved by the USA Food and Drug Administration (FDA) for detecting Aβ in clinic 11 . Another PiB analog, [ 18 F]Flutafuranol was developed for reducing the level of non- specifc white matter binding, which is benefcial for early diagnosis of AD 12, 13 . Moreover, there are two 18 F-labeled tracers with stilbene scaffold were also approved by the FDA, including [ 18 F]Florbetapir 14 and [ 18 F]Florbetaben 15 . However, an array of clinical results found that the FDA approved tracers all exhibited high uptakes in the white matter and slow clearance rate, which caused lower signal-to-noise ratio, per- plexing clinicians for exact distinguishing AD 16 . Consequently, there is an urgent need to enhance their pharmacokinetic properties in the brain. It is generally believed that lipophilicity is the main factor affecting the pharmacokinetic properties of probes, such as [ 18 F]Florbetapir and [ 18 F]Florbetaben, which are modifed with fuoro-polyethyleneglycol (FPEG) group to adjust lipophilicity. Increasing the lipophilicity (log P is ranging from 2 to 3.5) can increase the binding affnity toward Aβ and is benefcial to pass through the blood–brain barrier (BBB) 8, 17 , but it will deteriorate the pharmacokinetic properties. Whereas, the * Corresponding author. E-mail address: cmc@bnu.edu.cn (M. Cui). Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc https://doi.org/10.1016/j.bmc.2020.115884 Received 26 August 2020; Received in revised form 3 November 2020; Accepted 16 November 2020