Fragment-based labeling using condensation reactions of six potential 5-HT 7 R PET tracers
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Fragment‑based labeling using condensation reactions of six potential 5‑HT7R PET tracers Elina Tampio L’Estrade1,2,3 · Vladimir Shalgunov2,4 · Szabolcs Lehel4 · Ida Nymann Petersen4 · Christian Bernard Matthijs Poulie2 · Fraser G. Edgar2 · Balázs Volk5 · Tomas Ohlsson3 · Maria Erlandsson3 · Gitte M. Knudsen1,6 · Matthias M. Herth1,2,4 Received: 30 July 2020 / Accepted: 21 October 2020 © Akadémiai Kiadó, Budapest, Hungary 2020
Abstract In this work, a fragment-based labeling procedure was developed based on condensation reactions. Six 18F-labeled (arylpiperazinyl-butyl)oxindole derivatives were synthesized. These structures are interesting lead compounds with respect to development of a 5-HT7R PET tracer. They were radiolabeled in sufficient radiochemical yields, purities and molar activities for future in vivo evaluation in rodents. Keywords Arylpiperazines · Alkylation · Fluorine-18 · Carbon-11 · Screening · Positron emission tomography
Introduction Positron emission tomography (PET) is a valuable, noninvasive, molecular imaging technique that can be applied to characterize biological receptor or enzyme systems [1–3]. Today PET is routinely used in the clinic to assess disease stage and progression [4]. During the development of drugs acting in the central nervous system (CNS), the most Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10967-020-07475-0) contains supplementary material, which is available to authorized users. * Matthias M. Herth [email protected] 1
Neurobiology Research Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
2
Department for Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
3
Radiation Physics, Nuclear Medicine Physics Unit, Skånes University Hospital, Barngatan 3, 222 42 Lund, Sweden
4
Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
5
Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary
6
Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
important data obtained by PET is information enabling the determination of receptor occupancies [1, 2, 5]. Receptor occupancies can e.g. be used to estimate the optimal dose needed to maximize treatment efficacy, while minimizing side-effects [1, 5]. Developing a successful PET tracer is a challenging and complex process. Success rates are low, the process is timeconsuming and expensive because of its multifaceted nature [6, 7]. Development of a successful PET radiotracer cannot be reliably predicted from in vitro data and has thus far to be determined in vivo. For example, the blood–brain barrier permeability, the non-displaceable binding component and the respective kinetics of a tracer are parameters that are currently best estimated in vivo [5, 8, 9]. Consequent
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