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.
Ghaffari
M A
MA
MRC Group in the Radiation Sciences, Faculty of Medicine, University of Sherbrooke, Québec, Canada.
Ali
H
H
Rousseau
J
J
van Lier
J E
JE
D000814:Aniline Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005260:Female; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007462:Iodobenzenes / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011877:Radionuclide Imaging; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D000814:Aniline Compounds; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D007462:Iodobenzenes