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Synthesis and radiosynthesis of N5-[18F]fluoroethyl-Pirenzepine and its metabolite N5-[18F]fluoroethyl-LS 75

✍ Scribed by Patrick J. Riss; Vukic Soskic; Andre Schrattenholz; Frank Roesch

Publisher
John Wiley and Sons
Year
2009
Tongue
French
Weight
194 KB
Volume
52
Category
Article
ISSN
0022-2135

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✦ Synopsis

Abstract

The well established M~1~ selective muscarinergic antagonist Pirenzepine 11‐[2‐(4‐methyl‐piperazin‐1‐yl)‐acetyl]‐5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (1) exhibits an unusual behaviour in vivo, which cannot be explained with M~1~ antagonism exclusively. One of the aspects discussed is a specific interaction with poly ADP‐ribose polymerase (PARP‐1). 1 undergoes metabolism to form LS 75 5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (2). In order to study deviations in Pirenzepine efficacy from pure M~1~ binding in vivo using PET, appropriate positron emitter labelled analogues of 1 and 2 were synthesised. Non‐radioactive reference compounds 3 and 4 were tested for PARP‐1 inhibition. The n‐octanol–water partition coefficients of compounds 1, 2, 3 and 4 at pH 7.4 (logD~7.4~) were determined. Both, 3 and 4 were labelled with ^18^F via 2‐[^18^F]fluoroalkylation in position 5 of the benzodiazepinone moiety to obtain N^5^‐[^18^F]fluoroethyl Pirenzepine [^18^F]‐3 and N^5^‐[^18^F]fluoroethyl LS 75 [^18^F]‐4. Radiotracers [^18^F]‐3 and [^18^F]‐4 were obtained in radiochemical yields of 15±4 % and 30±5% after 120 and 110 min, respectively. Metabolism of both compounds was investigated in vitro in human and rat plasma, respectively. Compound 3 did not show activity as an inhibitor of PARP‐1. Contrary, 4 displays moderate PARP‐1 inhibition potency. The new radiotracer [^18^F]‐4 can be applied for molecular imaging using autoradiography and PET. Copyright © 2009 John Wiley & Sons, Ltd.

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