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

The well established M, 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, 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, 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 F-18 via 2-[F-18]fluoroalkylation in position 5 of the benzodiazepinone moiety to obtain N-5-[F-18]fluoroethyl Pirenzepine [F-18]-3 and N-5-[F-18]fluoroethyl LS 75 [F-18]-4. Radiotracers [F-18]-3 and [F-18]-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 [F-18]-4 can be applied for molecular imaging using autoradiography and PET.