STRUCTURAL MODIFICATION OF RECEPTOR-BINDING TC-99M COMPLEXES IN ORDERTO IMPROVE BRAIN UPTAKE

Low brain uptake is a generally accepted problem in developing technet ium-99m brain receptor imaging agents. For a class of potential 5-HT2A receptor-binding agents we tried to improve the original low brain up take of 0.4% injected dose (ID) in rats 5 min p.i. by modifying the li pophilic properties of the molecules. Because of the presence of a pro tonable nitrogen. which according to the pK(a) value leads to ionizati on of the molecule at blood pH, the pK(a) value was considered to be t he parameter most suitable for adjustment of lipophilicity. Insertion of ether-oxygen in the molecule of five candidates lowers the apparent pK(a) value from 10.0 to 8.3 and dramatically increases the brain upt ake to 1.3% ID at 5 min, The direct relationship between brain uptake and apparent pK(a) cannot be simply explained by the increase in the p K(a)-governed proportion of the neutral species.