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Synthesis and Pharmacological Characterization of 4-[¹²⁵I]-N-(N-Benzylpiperidin-4-yl)-4-iodobenzamide: A High Affinity Receptor Ligand for Potential Imaging of Breast Cancer¹

Radiology Research, Department of Radiology, George Washington University Medical Center, Washington, DC 20037 [C. S. J., M. E. G.]; Unit on Receptor Biochemistry and Pharmacology, Laboratory of Medicinal Chemistry, NIDDK, NIH, Bethesda, Maryland 20892 [B. J. V., W. D. B.]; Departments of Radiology, Medicinal Chemistry and Neurosurgery, University of Minnesota, Minneapolis, Minnesota 55455 [R. B. L., S. M. N. E.]; and Biomarkers and Prevention Research Branch, National Cancer Institute, Rockville, Maryland 20850 [T. W. M.]

The synthesis of [¹²⁵I]-N-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-[¹²⁵I]BP), a novel radiopharmaceutical that possess high affinity for both -1 and -2 receptor subtypes, and its binding characteristics to MCF-7 breast cancer cells are described. To obtain high yields (with high specific activity) of radioiodinated ligand, (N-benzylpiperidin-4-yl)-4-tributylstannyl benzamide was synthesized. Radiolabeled 4-[¹²⁵I]BP was prepared from tri-butylstannyl precursor with the use of chloramine-T or hydrogen peroxide as an oxidizing agent in high yields (71–86%). The competition binding studies of 4-[¹²⁵I]BP in MCF-7 breast tumor cells with haloperidol and DTG (known ligands) showed a dose-dependent displacement and high affinity binding (K_i = 4.6 and 56 nM, respectively), demonstrating that receptors are expressed in MCF-7 breast tumor cells. Scatchard analysis of 4-[¹²⁵I]BP binding in MCF-7 cells revealed saturable binding, with a K_d = 26 nM and a B_max = 4000 fmol/mg protein. Furthermore, the Scatchard analysis of [³H]DTG binding in MCF-7 cells gave a K_d of 24.5 nM and a B_max of 2071 fmol/mg of protein. The biodistribution and clearance of 4-[¹²⁵I]BP was studied in rats. The radiopharmaceutical cleared quickly from the blood pool but rather slowly from the hepatobiliary system. The in vivo specificity was demonstrated by blocking the receptor binding in the presence of haloperidol. A decrease of 55, 63, 43, and 68% was found at 1 h postinjection in brain, kidney, heart, and lung, respectively. These results demonstrate that a high density of receptors are expressed in MCF-7 cells and that radioiodinated 4-IBP may be useful for imaging breast cancer by targeting sites.

¹ This work was supported in part by Department of Radiology, George Washington University Medical Center, and NIH Grant CA58496.

² To whom requests for reprints should be addressed, at George Washington University Medical Center, 2300 I Street, N.W., 661 Ross Hall, Washington, DC 20037.

Received 1/26/95. Accepted 5/16/95.

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