Stereoselective synthesis, in vitro, and initial in vivo evaluation of 1-methylpiperidin-4-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IPIP): a novel radioiodinated molecular probe with high affinity for the muscarinic receptor.
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 M(1) to M(2) 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/micromol, and radiochemical purities >97%. In vivo the Z-isomers demonstrated high uniform cerebral uptake suggesting non-subtype selective binding. In contrast, E-R-IPIP, after allowing a low uptake in M(2) rich areas to clear, demonstrated a retention of activity in M(1) and M(4) 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.
McPherson
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Nuclear Medicine Group, Life Sciences Division, Oak Ridge National Laboratory (ORNL), Post Office Box 2008, Building 4501, Oak Ridge, TN 37831-6229, USA. mcphersod@CSR.NIH.GOV
Breeden
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Beets
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Luo
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Sood
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Knapp
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D000818:Animals; D005260:Female; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010648:Phenylacetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
C447162:1-methylpiperidin-4-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate; D015335:Molecular Probes; D010648:Phenylacetates; D010880:Piperidines; D011976:Receptors, Muscarinic; D011813:Quinuclidinyl Benzilate