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J Med Chem. 1998 Jul 2;41(14):2445-50.

Substituted halogenated arylsulfonamides: a new class of sigma receptor binding tumor imaging agents.

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Radiopharmaceutical Chemistry Section, Department of Radiology, The George Washington University Medical Center, Washington, D.C. 20037, USA.


The discovery of a series of novel halogenated arylsulfonamides (HAS) as new sigma receptor binding tumor imaging agents is described. Several substituted halogenated sulfonamides have been prepared and characterized. Target compounds were examined for their affinity for sigma1 and sigma2 receptor subtypes using guinea pig brain membranes and rat liver membranes, respectively. A number of substituted halogenated sulfonamides displayed subnanomolar affinities for sigma1 sites and low nanomolar affinities for sigma2 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 sigma receptor binding ligands confirmed its sigma 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 sigma1 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.

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