Biological evaluation of ring- and side-chain-substituted m-iodobenzylguanidine analogues

A number of ring- and side-chain-substituted m-iodobenzylguanidine analogue s 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 pol ar hydroxyl, amino, and nitro substitutents. Most of the derivatives showed reasonable stability up to 24 h in PBS at 37 degreesC. While N-1-hydroxy-N -3-3-[I-131]iodobenzylguanidine and 3,4-dihydroxy-5-[I-131]iodobenzylguanid ine generated a more nonpolar product in addition to the free iodide, 3-[I- 131]iodo-4-nitrobenzylguanidine decomposed to a product more polar than the parent compound. The specific uptake of 4-chloro-3[I-131]iodobenzylguanidi ne, 3-[I-131]iodo-4-nitrobenzylguanidine, and N-1-hydroxy-N-3-3-[I-131]iodo benzylguanidine by SK-N-SH human neuroblastoma cells in vitro, relative to that of m-[I-125]iodobenzylguanidine, was 117 +/- 10%, 50 +/- 4%, and 12 +/ - 2%, respectively. The specific uptake of the known m-iodobenzylguanidine analogues 4-hydroxy-3-[I-131]iodobenzylguanidine and 4-amino-3-[I-131]iodob enzylguanidine was 80 +/- 4% and 66 +/- 4%, respectively. None of the other m-iodobenzylguanidine derivatives showed any significant specific uptake b y SK-N-SH cells. Heart uptake of 4-chloro-3-[I-131]iodobenzylguanidine in n ormal mice was higher than that of m-[I-125]iodobenzylguanidine at later ti me points (11 +/- 1%, ID/g versus 3 +/- 1% ID/g at 24 h; p < 0.05) while up take of 3-[I-131]iodo-4-nitrobenzylguanidine and of N-1-hydroxy-N-3-3-[I-13 1]iodobenzylguanidine in the heart was lower than that of m-iodobenzylguani dine at all time points. In accordance with the in vitro results, none of t he other novel m-iodobenzylguanidine derivatives showed any significant myo cardial or adrenal uptake in vivo.