title: Preclinical evaluation of an 131I-labeled benzamide for targeted radiotherapy of metastatic melanoma.
abstract: Radiolabeled benzamides are attractive candidates for targeted radiotherapy of metastatic melanoma as they bind melanin and exhibit high tumor uptake and retention. One such benzamide, N-(2-diethylamino-ethyl)-4-(4-fluoro-benzamido)-5-iodo-2-methoxy-benzamide (MIP-1145), was evaluated for its ability to distinguish melanin-expressing from amelanotic human melanoma cells, and to specifically localize to melanin-containing tumor xenografts. The binding of [(131)I]MIP-1145 to melanoma cells in vitro was melanin dependent, increased over time, and insensitive to mild acid treatment, indicating that it was retained within cells. Cold carrier MIP-1145 did not reduce the binding, consistent with the high capacity of melanin binding of benzamides. In human melanoma xenografts, [(131)I]MIP-1145 exhibited diffuse tissue distribution and washout from all tissues except melanin-expressing tumors. Tumor uptake of 8.82% injected dose per gram (ID/g) was seen at 4 hours postinjection and remained at 5.91% ID/g at 24 hours, with tumor/blood ratios of 25.2 and 197, respectively. Single photon emission computed tomography imaging was consistent with tissue distribution results. The administration of [(131)I]MIP-1145 at 25 MBq or 2.5 GBq/m(2) in single or multiple doses significantly reduced SK-MEL-3 tumor growth, with multiple doses resulting in tumor regression and a durable response for over 125 days. To estimate human dosimetry, gamma camera imaging and pharmacokinetic analysis was performed in cynomolgus monkeys. The melanin-specific binding of [(131)I]MIP-1145 combined with prolonged tumor retention, the ability to significantly inhibit tumor growth, and acceptable projected human dosimetry suggest that it may be effective as a radiotherapeutic pharmaceutical for treating patients with metastatic malignant melanoma.
authors.affiliation: Molecular Insight Pharmaceuticals, Cambridge, Massachusetts 02142, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.forename: John A
authors.initials: JA
authors.lastname: Barrett
authors.forename: John C
authors.initials: JC
authors.lastname: Marquis
authors.forename: Jianqing
authors.initials: J
authors.lastname: Chen
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Maresca
authors.forename: Marie
authors.initials: M
authors.lastname: Boyd
authors.forename: Kenneth
authors.initials: K
authors.lastname: Gage
authors.forename: Sridhar
authors.initials: S
authors.lastname: Nimmagadda
authors.forename: James F
authors.initials: JF
authors.lastname: Kronauge
authors.forename: Matthias
authors.initials: M
authors.lastname: Friebe
authors.forename: Ludger
authors.initials: L
authors.lastname: Dinkelborg
authors.forename: James B
authors.initials: JB
authors.lastname: Stubbs
authors.forename: Michael G
authors.initials: MG
authors.lastname: Stabin
authors.forename: Rob
authors.initials: R
authors.lastname: Mairs
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D008543:Melanins / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D015996:Survival Rate; D015899:Tomography, Emission-Computed, Single-Photon; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D007457:Iodine Radioisotopes; D008543:Melanins; C550120:N-(2-diethylaminoethyl)-4-(4-fluorobenzamido)-5-iodo-2-methoxybenzamide; D019275:Radiopharmaceuticals