Development of potential selective and reversible pyrazoline based MAO-B inhibitors as MAO-B PET tracer precursors and reference substances for the early detection of Alzheimer’s disease Catharina Neudorfer a,b,⇑ , Karem Shanab a,b , Andreas Jurik c , Veronika Schreiber d , Carolina Neudorfer b , Chrysoula Vraka a,e , Eva Schirmer b , Wolfgang Holzer b , Gerhard Ecker c , Markus Mitterhauser a , Wolfgang Wadsak a , Helmut Spreitzer b,⇑ a Medical University of Vienna, Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Waehringer Guertel 18-20, 1090 Vienna, Austria b University of Vienna, Faculty of Life Sciences, Department of Pharmaceutical Chemistry, Division of Drug Synthesis, Althanstraße 14, 1090 Vienna, Austria c University of Vienna, Faculty of Life Sciences, Department of Pharmaceutical Chemistry Division of Drug Design and Medicinal Chemistry, Althanstraße 14, 1090 Vienna, Austria d University of Vienna, Faculty of Life Sciences, Division of Clinical Pharmacy and Diagnostics, Althanstraße 14, 1090 Vienna, Austria e University of Vienna, Department of Nutritional Sciences, Althanstraße 14, 1090 Vienna, Austria article info Article history: Received 13 June 2014 Revised 25 July 2014 Accepted 30 July 2014 Available online xxxx Keywords: MAO-B Alzheimer’s disease PET Pyrazoline derivatives Molecular imaging abstract Since high MAO-B levels are present in early stages of AD, the MAO-B system can be designated as an appropriate and prospective tracer target of molecular imaging biomarkers for the detection of early AD. According to the preceding investigations of Mishra et al. the aim of this work was the development of a compound library of selective and reversible MAO-B inhibitors by performing bioisosteric modifica- tions of the core structure of 3-(anthracen-9-yl)-5-phenyl-4,5-dihydro-1H-pyrazoles. In conclusion, 13 new pyrazoline based derivatives have been prepared, which will serve as precursor substances for future radiolabeling as well as reference compounds for the investigation of increased MAO-B levels in AD. Ó 2014 Elsevier Ltd. All rights reserved. Currently, two distinct enzymatic isoforms of MAO (mono- amine oxidase) have been characterized, namely MAO-A and MAO-B. Although they share a high sequence similarity of about 70%, they differ in their tissue distribution, substrate specificity and inhibitor selectivity. 1 MAO-B is prevalent in lymphocytes and platelets and displays high concentration levels in the human brain, mostly predominant in serotonergic and histaminergic neu- rons, as well as in astrocytes. Since MAO-B plays a pivotal role as degradation enzyme in the human brain, it is involved in a variety of neurological diseases, such as attention deficit hyperactivity dis- order (ADHD), Tourette’s syndrome, amyotrophic lateral sclerosis (ALS), Huntington’s disease and age-related neurological disorders like Parkinson’s disease (PD) and Alzheimer’s disease (AD). 2 As a chronic, progressive neurodegenerative disorder, AD affects millions of people worldwide, causing loss of mental and physical functions. 3,4 Since increased MAO-B levels are measured even in early stages of AD, 5–10 the MAO-B system exhibits a promising and prospective tracer target for molecular imaging of AD and especially early stage AD. 10–12 The state of the art method for the visualization and quantification of receptor and enzyme systems in vivo is PET (positron emission tomography), a technique which allows to quantify in vivo processes non-invasively. In the context of developing new PET radioligands for the detection of MAO-B in AD, their precursors for radiolabeling, and reference compounds for preclinical testing, first needed to be prepared. According to the results of Mishra et al. 13 5-(anthracen-9-yl)-3- phenyl-4,5-dihydro-1H-pyrazoles (Fig. 1) represent highly selec- tive and extremely potent, reversible MAO-B inhibitors. They do not only display a superior affinity towards MAO-B, but also pro- vide a high MAO-B versus MAO-A selectivity ratio. Additionally, these compounds display docking scores superior > 12.5 and pre- dicted K i values in nanomolar ranges, what makes them at least 100 times more potent than the positive control, selegiline. 13 It should be noted that the chemical structure in the original article of Mishra et al. 13 depicts the double bond of the pyrazoline ring in the false position. Figure 1 shows the correct chemical structure, which is expected according to the preceding synthesis. http://dx.doi.org/10.1016/j.bmcl.2014.07.085 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. Tel.: +43 4277 55629; fax: +43 4277 855629 (C.N.); tel.: +43 4277 55621; fax: +43 4277 855621 (H.S.). E-mail addresses: catharina.neudorfer@gmail.com (C. Neudorfer), helmut.spreit zer@univie.ac.at (H. Spreitzer). Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Please cite this article in press as: Neudorfer, C.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.07.085