SDZ-NKT-343

We have identified a successful family of simple P-stereogenic N-phosphine-phosphite ligands for the Rh-catalyzed asymmetric hydrogenation of olefins. These catalysts show excellent enantiocontrol for α-dehydroamino acid derivatives and α-enamides (ee's up to >99%) and promising results for the more challenging β-analogues (ee's up to 80%). The usefulness of these catalytic systems was further demonstrated with the synthesis of several valuable precursors for pharmacologically active compounds, with ee's at least as high as the best ones reported previously (up to >99%).

Neurotransmission mediated by substance P (SP) and NK1receptor has been implicated in the pathophysiology of analgesia, emesis and diverse neuropsychiatric conditions including depression and anxiety disorder. Several lines of clinical trials using NK1receptor antagonists have been conducted to date, and the efficiency of preclinical assessments for proof of concept and dose optimization could be greatly increased by configuring an in vivo analytical system that permits quantitative mapping of NK1receptors in the brains of small‐size laboratory animals expressing “human‐like” NK1receptors. Hence, we investigated the applicability of experimental animals, ranging from rodents to primates, to positron emission tomographic (PET) measurements with [18F]fluoroethyl‐SPA‐RQ, a modification of a recently established radioligand for NK1receptors. A pharmacokinetic assay could be performed for a rhesus monkey in an awake condition, which allows the circumvention of influences of anesthesia on SP neurotransmission. Coregistration of PET and magnetic resonance images acquired by small‐animal‐dedicated devices enabled detailed localization of NK1receptors in the gerbil and marmoset brains. The present study also revealed the potentials of SDZ NKT 343 as an antagonist for central NK1receptors. In conjunction with additional in vitro and ex vivo autoradiographic observations, our in vivo results have demonstrated a similarity in the binding pattern among the animals examined, justifying cross‐species extrapolation of PET findings on the SP‐NK1pathway. Synapse 61:205–215, 2007. © 2007 Wiley‐Liss, Inc.