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.