Biological Evaluation of Ring- and Side-Chain-Substituted m-Iodobenzylguanidine Analogues

• Published in: Bioconjugate chemistry 2001-09, Vol.12 (5), p.798-806
• Main Authors: Vaidyanathan, Ganesan, Shankar, Sriram, Affleck, Donna J, Welsh, Philip C, Slade, Susan K, Zalutsky, Michael R
• Format: Article
• Language: English
• Subjects: 3-Iodobenzylguanidine - analogs & derivatives; 3-Iodobenzylguanidine - chemical synthesis; 3-Iodobenzylguanidine - pharmacokinetics; Adrenal Glands; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Cell Membrane Permeability; Drug Stability; Guanidines - chemical synthesis; Guanidines - pharmacokinetics; Heart; Humans; Male; Mice; Mice, Inbred BALB C; Organ Specificity; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - pharmacokinetics; Structure-Activity Relationship; Tissue Distribution; Tumor Cells, Cultured
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc010032r

A number of ring- and side-chain-substituted m-iodobenzylguanidine analogues were evaluated for their lipophilicity, in vitro stability, uptake by SK-N-SH human neuroblastoma cells in vitro, and biodistribution in normal mice. As expected, the lipophilicity of m-iodobenzylguanidine increased when a halogen was introduced onto the ring and decreased with the addition of polar hydroxyl, amino, and nitro substitutents. Most of the derivatives showed reasonable stability up to 24 h in PBS at 37 °C. While N 1-hydroxy-N 3-3-[131I]iodobenzylguanidine and 3,4-dihydroxy-5-[131I]iodobenzylguanidine generated a more nonpolar product in addition to the free iodide, 3-[131I]iodo-4-nitrobenzylguanidine decomposed to a product more polar than the parent compound. The specific uptake of 4-chloro-3-[131I]iodobenzylguanidine, 3-[131I]iodo-4-nitrobenzylguanidine, and N 1-hydroxy-N 3-3-[131I]iodobenzylguanidine by SK-N-SH human neuroblastoma cells in vitro, relative to that of m-[125I]iodobenzylguanidine, was 117 ± 10%, 50 ± 4%, and 12 ± 2%, respectively. The specific uptake of the known m-iodobenzylguanidine analogues 4-hydroxy-3-[131I]iodobenzylguanidine and 4-amino-3-[131I]iodobenzylguanidine was 80 ± 4% and 66 ± 4%, respectively. None of the other m-iodobenzylguanidine derivatives showed any significant specific uptake by SK-N-SH cells. Heart uptake of 4-chloro-3-[131I]iodobenzylguanidine in normal mice was higher than that of m-[125I]iodobenzylguanidine at later time points (11 ± 1% ID/g versus 3 ± 1% ID/g at 24 h; p < 0.05) while uptake of 3-[131I]iodo-4-nitrobenzylguanidine and of N 1-hydroxy-N 3-3-[131I]iodobenzylguanidine in the heart was lower than that of m-iodobenzylguanidine at all time points. In accordance with the in vitro results, none of the other novel m-iodobenzylguanidine derivatives showed any significant myocardial or adrenal uptake in vivo.