Synthesis, In Vitro Binding, and Tissue Distribution of Radioiodinated 2-[ 125I] N-( N-Benzylpiperidin-4-yl)-2-Iodo Benzamide, 2-[ 125I]BP: A Potential σ Receptor Marker for Human Prostate Tumors

Abstract

The preclinical evaluation of a σ receptor–specific radiopharmaceutical that binds to human prostate tumor cells with a high affinity is described. We have synthesized and radioiodinated 2-[ 125I]- N-( N-benzylpiperidin-4-yl)-2-iodobenzamide (2-[ 125I]BP) that possesses high affinity for both σ-1 and σ-2 receptor subtypes that are expressed on a variety of tumor cells. 2-IBP was synthesized, purified and characterized by routine spectroscopic and analytical methods. Radioiodination was accomplished using an oxidative iododestannylation reaction in the presence of chloramine T in high yields (76%–93%) with a very high-specific activity (1700–1900 Ci/mmol). The in vitro competition binding studies of 2-[ 125I]BP with various σ receptor ligands in LnCAP human prostate tumor cells showed a dose-dependent saturable binding. The inhibition constants (K i, nM) for binding of 2-[ 125I]BP to human prostate tumor cells for 4-IBP, haloperidol and 2-IBP were 4.09, 6.34 and 1.6 nM, respectively. The clearance of 2-[ 125I]BP, in Sprague–Dawley rats, was rapid from the blood pool, other normal tissues and the total body. Tissue distribution studies in nude mice bearing human prostate tumor (DU-145) also showed a fast clearance from normal organs. The tumor had the highest percentage of injected dose per gram (%ID/g) of all tissues at 4 h as well as 24 h (2.0 ± 0.05 and 0.147 ± 0.038 ID/g, respectively) postinjection. The in vivo receptor binding specificity was demonstrated using haloperidol (a known high-affinity σ receptor ligand). A significant decrease (>50%, p = 0.001) was observed in tumor concentration when haloperidol was used as a blocking agent. The high affinity of 2-[ 125I]BP for σ receptor–binding sites, its fast in vivo clearance from normal organs and its high uptake and retention in tumor implies that 2-[ 123I]BP or 2-[ 131I]BP may be a promising tracer for noninvasive imaging of human prostate tumors.