Synthesis of (R, R)123I‐QNB, A spect imaging agent for cerebral muscarinic acetylcholine receptors in vivo

Abstract

AbstractThe high‐affinity muscarinic receptor antagonist (R,R) I‐QNB(1) [(R)‐(‐)‐1‐Azabicyclo [2.2.2]oct‐3‐yl‐ (R) ‐ (+) ‐ α‐hydroxy‐α‐(4‐[127I]iodophenyl)‐α‐phenyl Acetate (6a)] has been labeled with iodine‐123 to give a suitable ligand for SPECT (Single photon emission computed tomography) imaging of the human brain. The radiolabeling is achieved using a copper(I) assisted nucleophilic exchange mechanism(2) to give high specific activity (R,R)123I‐QNB in reasonable overall yield (36%). The radiolabeling reaction is carried out in the presence of excess reducing agent and the product (R,R)123I‐QNB purified on a Sep‐Pak cartridge eliminating the need for h.p.l.c. purification the synthesis of the precursor (127I‐QNB) for the radiolabeling step is a modification of the procedure reported by Rzeszotarski et. al(3) (R)‐α‐Hydroxy‐α‐(4‐nitrophenyl)‐α‐phenylacetic acid was produced from 4‐nitrobenzophenone and resolved as reported. The methyl ester of the acid was synthesised then the nitro group converted to an amino group to give Methyl, (R) ‐α‐hydroxy‐α‐ (4‐aminophenyl) ‐a‐ phenyl acetate. The iodo compound Methyl, (R) ‐α‐hydroxy‐α‐ (4‐iodophenyl)‐α‐phenyl acetate was produced from the amino compound via the diazonium salt. Transesterification of the iodo compound with (R) ‐3‐quinuclidinof gave (R, R) ‐f271‐QNB.The (R,R) 123I‐QNB produced has been successfully used to image muscarinic receptors in patients suffering from Alzheimers disease.