Synthesis and tissue distribution of substituted [125I]iodophenylamine derivatives: possible brain imaging agents

The synthesis and brain uptake in mice of the radioiodinated derivatives of N,N-dimethyl-N'-(iododimethoxyphenyl)-1,3-propanediamine, as well as the N-substituted derivatives of (iodoalkylphenyl)isopropyl, iodoalkylphenylethylamine and 3,4-(methylenedioxy)phenyl-amphetamine (MDA) are described. These compounds contain structural features of both IMP and HIPDM, the cerebral perfusion agents currently in clinical use. The radiolabeled analogs were obtained via the [125I]I exchange method, or by [125I]NaI treatment of the iodo-free precursor in the presence of an oxidant. Following intravenous injection in mice, all compounds showed important radioactivity concentrations in the lungs and kidneys. The N-substituted (iodoalkylphenyl)isopropyl and iodoalkylphenyl-ethylamine derivatives displayed a high initial brain uptake (> 10% IDg-1) followed by a rapid clearance phase, resulting in lower brain-to-blood ratios as those reported for IMP and HIPDM. In contrast, N,N-dimethyl-N'-(iododimethyphenyl)-1,3-propanediamine derivatives featuring the iodo substituent on the benzene carbon adjacent to the methyl amine group and the methoxy substituents on the 2,5- or 2,4-positions, showed low but more persistant brain uptake. Combined with fast blood clearance, this resulted in high brain-to-blood ratios at later time points. Among all compounds tested, the highest brain-to-blood ratio was observed with compound N,N-dimethyl-N'-(6-iodo-3,4-dimethyoxyphenyl)-1,3-propanediamine (27e), reaching a maximum of > 20 at 12 h post-injection.