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

The well established M₁ selective muscarinergic antagonist Pirenzepine 11‐2‐(4‐methyl‐piperazin‐1‐yl)‐acetyl]‐5,11‐dihydro‐benzoe]pyrido3,2‐b]1,4]diazepin‐6‐one (1) exhibits an unusual behaviour in vivo, which cannot be explained with M₁ 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‐benzoe]pyrido3,2‐b]1,4]diazepin‐6‐one (2). In order to study deviations in Pirenzepine efficacy from pure M₁ 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 ¹⁸F via 2‐¹⁸F]fluoroalkylation in position 5 of the benzodiazepinone moiety to obtain N⁵‐¹⁸F]fluoroethyl Pirenzepine ¹⁸F]‐3 and N⁵‐¹⁸F]fluoroethyl LS 75 ¹⁸F]‐4. Radiotracers ¹⁸F]‐3 and ¹⁸F]‐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 ¹⁸F]‐4 can be applied for molecular imaging using autoradiography and PET. Copyright © 2009 John Wiley & Sons, Ltd.