Synthesis and biologic studies of iodinated (125I/127I) ethidium

1-Methylpiperidin-4-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IPIP, Fig. 1) was investigated as a potential radioiodinated molecular probe targeted to the muscarinic receptor complex. The IPIP stereoisomers were synthesized via a chiral intermediate in >95% enantiomeric excess. The R-isomers demonstrated a M1 to M2 subtype selectivity of approximately 3 to 1 and the S-isomers demonstrated non-subtype selective binding in vitro. IPIP was radiolabeled with iodide-125 with an average radiochemical yield of 74.4% (±14.8, N = 5), specific activities >800 mCi/mu mol, and radiochemical purities > 97%. In vivo the Z-isomers demonstrated high uniform cerebral uptake suggesting nonsubtype selective binding. In contrast, E-R-IPIP, after allowing a low uptake in M2 rich areas to clear, demonstrated a retention of activity in M1 and M4 rich cerebral regions. In addition, the cerebral uptake of E-R-IPIP and Z-S-IPIP were inhibited by 70¯90% via pretreatment with R-QNB, an established muscarinic antagonist. An ex vivo metabolism study demonstrated Z-S-IPIP was stable at the receptor site with an absence of radiolabeled metabolites.