SYNTHESIS OF (R,R)I-123-QNB, A SPECT IMAGING AGENT FOR CEREBRAL MUSCARINIC ACETYLCHOLINE-RECEPTORS INVIVO

The high-affinity muscarinic receptor antagonist (R,R)I-QNB(1) [(R)-(-)-1-Azabicyclo[2.2.2]oct-3-yl-(R)-(+)-alpha-hydroxy-alpha-(4-[I-127]iodophenyl)-alpha-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)I-123-QNB in reasonable overall yield (36%). The radiolabeling reaction is carried out in the presence of excess reducing agent and the product (R,R)I-123-QNB purified on a Sep-Pak cartridge eliminating the need for h.p.l.c. purification The synthesis of the precursor (I-127-QNB) for the radiolabeling step is a modification of the procedure reported by Rzeszotarski et. al..(3) (R)-alpha-Hydroxy-alpha-(4-nitrophenyl)-alpha-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)-alpha-hydroxy-alpha-(4-aminophenyl)-alpha-phenyl acetate. The iodo compound Methyl, (R)-alpha-hydroxy-alpha-(4-iodophenyl)-alpha-phenyl acetate was produced from the amino compound via the diazonium salt. Transesterification of the iodo compound with (R)-3-quinuclidinol gave (R,R)-I-127-QNB. The (R,R)I-123-QNB produced has been successfully used to image muscarinic receptors in patients suffering from Alzheimers disease.