Biological Evaluation of Ring- and Side-Chain-Substituted m-Iodobenzylguanidine Analogues
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- 作者：Ganesan Vaidyanathan ; Sriram Shankar ; Donna J. Affleck ; Philip C. Welsh ; Susan K. Slade ; and Michael R. Zalutsky
- 刊名：Bioconjugate Chemistry
- 出版年：2001
- 出版时间：September 2001
- 年：2001
- 卷：12
- 期：5
- 页码：798 - 806
- 全文大小：101K
- 年卷期：v.12,no.5(September 2001)
- ISSN：1520-4812
文摘
A number of ring- and side-chain-substituted m-iodobenzylguanidine analogues were evaluated fortheir lipophilicity, in vitro stability, uptake by SK-N-SH human neuroblastoma cells in vitro, andbiodistribution in normal mice. As expected, the lipophilicity of m-iodobenzylguanidine increased whena 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 N1-hydroxy-N3-3-[131I]iodobenzylguanidine and 3,4-dihydroxy-5-[131I]iodobenzylguanidinegenerated a more nonpolar product in addition to the free iodide, 3-[131I]iodo-4-nitrobenzylguanidinedecomposed to a product more polar than the parent compound. The specific uptake of 4-chloro-3-[131I]iodobenzylguanidine, 3-[131I]iodo-4-nitrobenzylguanidine, and N1-hydroxy-N3-3-[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 theknown 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-iodobenzylguanidinederivatives 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 timepoints (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 N1-hydroxy-N3-3-[131I]iodobenzylguanidine in the heart was lower than thatof m-iodobenzylguanidine at all time points. In accordance with the in vitro results, none of the othernovel m-iodobenzylguanidine derivatives showed any significant myocardial or adrenal uptake in vivo.
C. While N1-hydroxy-N3-3-[131I]iodobenzylguanidine and 3,4-dihydroxy-5-[131I]iodobenzylguanidinegenerated a more nonpolar product in addition to the free iodide, 3-[131I]iodo-4-nitrobenzylguanidinedecomposed to a product more polar than the parent compound. The specific uptake of 4-chloro-3-[131I]iodobenzylguanidine, 3-[131I]iodo-4-nitrobenzylguanidine, and N1-hydroxy-N3-3-[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 theknown 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-iodobenzylguanidinederivatives 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 timepoints (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 N1-hydroxy-N3-3-[131I]iodobenzylguanidine in the heart was lower than thatof m-iodobenzylguanidine at all time points. In accordance with the in vitro results, none of the othernovel m-iodobenzylguanidine derivatives showed any significant myocardial or adrenal uptake in vivo.