Preparation and Properties of (R)-(−)-1-Azabicyclo[2.2.2]Oct-3-yl-(R)-(+)-α-Hydroxy-α-(4-[125l]Iodophenyl)-α-Phenyl Acetate and (R)-(−)-1-Azabicyclo[2.2.2]Oct-3-Yl-(S)-(−)-α-hydroxy-α-(4-[125l]iodophenyl)-α-phenyl acetate as potential radiopharmaceuticals

• Published in: Journal of pharmaceutical sciences 1989-10, Vol.78 (10), p.833-836
• Main Authors: Cohien, Victor I., Rzeszotarski, Waclaw J., Gibson, Raymond E., Fan, Linda H., Reba, Richard C.
• Format: Article
• Language: English
• Subjects: Animals; Chemical Phenomena; Chemistry; Corpus Striatum - diagnostic imaging; Exact sciences and technology; Female; Iodine Radioisotopes; Noncondensed benzenic compounds; Organic chemistry; Preparations and properties; Quinuclidines - pharmacology; Quinuclidinyl Benzilate - analogs & derivatives; Quinuclidinyl Benzilate - chemical synthesis; Quinuclidinyl Benzilate - pharmacokinetics; Quinuclidinyl Benzilate - pharmacology; Radionuclide Imaging; Rats; Rats, Inbred Strains
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600781011

rac-4-Nitrobenzilic acid was synthesized and resolved with quinidine and quinine to give the corresponding (R)- and (S)-salts. The resolved diastereomeric salts were converted to (R)- and (S)-4-nitrobenzilic acids and subsequent esterification gave their corresponding ethyl esters. Transesterification with (R)-(−)-3-quinuclidinol afforded (R)-(−)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-α-hydroxy-α-(4-nitrophenyl)-α phenyl acetate and (R)-(−)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(−)-α-hydroxy-α-(4-nitrophenyl)-α-phenyl acetate. After hydrogenation, the (R,R)- and (R,S)-amines were converted to the respective triazene derivatives. The triazene derivatives reacted with sodium [125l]iodide to give (R)-(−)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-α-hydroxy-α-(4-[125l]iodophenyl)-α-phenyl acetate and (R)-(−)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(−)-α-hydroxy-α-(4-[125l]iodophenyl)-α-phenyl acetate. The evaluation of their affinities to muscarinic acetylcholine receptors (MAcChR) shows that (R)-(−)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(−)-α-hydroxy-α-(4-[125 I]iodophenyl)-α-phenyl acetate exhibits an affinity for the MAcChR from corpus striatum that is approximately threefold lower than that of (R)-(−)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-α-hydroxy-α-(4-[125l]iodophenyl)-α-phenyl acetate.