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.