Brain localization and octanol/water PC-pH profiles of radioiodinated amines: Evidences against ''pH shift'' mechanism

''pH shift'' has been suggested as a mechanism for brain uptake of some radiolabeled diamines. The steepness of the octanol/water partition coefficient (PC)-pH profile at pH 7.4-7 was used as criterion for good brain uptake and retention. The authors have investigated whether this mechanism can be applied to radioiodinated amines in general, using benzylamine and amphetamine derivatives. I-125 labeled p-iodoamphetamine (I), N-isopropyl-p-iodoamphetamine (II), N-t-butyl-o-iodobenzylamine (III), o-iodoaphetamine (IV), and N-isopropyl-o-iodoamphetamine (V) were prepared via routine radioexchange reaction. The vivo distribution in rats and octanol/water PC-pH profiles for I-V were then obtained. All five showed good initial brain uptake at 5 min; however, only I and II exhibited retention of activity at 1 hour. The blood background for all the compounds was low at both times. However, there was no correlation between the PC-pH profiles and brain retention. III was equivalent to II, IV was similar to I, III and V were steeper than I and II was much steeper than I. Clearly, the PC-pH profile, and thus ''pH shift'' mechanism, cannot be used in the prediction of brain uptake characteristics of amines. These findings along with the clinical findings that no increased uptake of II was seen around the periphery of cerebral infarction (an area where decreased pH should be found due to anerobic glycolysis) strongly suggest that ''pH shift'' cannot be a viable brain uptake mechanism for radiolabeled amines. The brain uptake of amines is consistent with the presence of high-capacity non-specific amine binding sites in the brain