| Autor: |
John, C. S., Lim, B. B., Vilner, B. J., Geyer, B. C., Bowen, W. D. |
| Zdroj: |
Journal of Medicinal Chemistry; July 2, 1998, Vol. 41 Issue: 14 p2445-2450, 6p |
| Abstrakt: |
The discovery of a series of novel halogenated arylsulfonamides (HAS) as new σ receptor binding tumor imaging agents is described. Several substituted halogenated sulfonamides have been prepared and characterized. Target compounds were examined for their affinity for σ1 and σ2 receptor subtypes using guinea pig brain membranes and rat liver membranes, respectively. A number of substituted halogenated sulfonamides displayed subnanomolar affinities for σ1 sites and low nanomolar affinities for σ2 subtype receptors. A limited structure−activity relationship study of this chemical series is discussed. The radioiodination (I-125) of one congener member (4-[125I]iodo-N-[2-(1-piperidinyl)ethyl]benzenesulfonamide, 4-[125I]IPBS) was accomplished in high yields. The in vitro competition binding studies of 4-[125I]IPBS in guinea pig brain membranes with σ receptor binding ligands confirmed its σ pharmacology. The rank order of potency was BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) > 4-IPBS > haloperidol > (+)-pentazocine > DTG (1,3-di-o-tolylguanidine) > (−)-pentazocine. The inhibition constants (IC50) were 0.70, 1.46, 6.28, 10.4, 87.2, and 152 nM, respectively, and are consistent with labeling of σ1 receptors. The tumor imaging potential of 4-[125I]IPBS was studied in C57 black mice bearing B16 melanoma xenograft. A high tumor uptake of 4-[125I]IPBS was observed (7.40% ID/g) at 1 h postinjection. The wash out of activity from the tumor was slow at 6 h postinjection (7.22% ID/g). The tumor also had the highest amount of radioactivity (1.54% ID/g) at 24 h postinjection. These results demonstrate that radiohalogenated benzenesulfonamides could be a potentially useful class of compounds in nuclear oncologic scintigraphy. |
| Databáze: |
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