Preparation and Biologic Evaluation of a Novel Radioiodinated Benzylpiperazine, 123I-MEL037, for Malignant Melanoma

Abstract

Radiopharmaceuticals that can target the random metastatic dissemination of melanoma tumors may present opportunities for imaging and staging the disease as well as potential radiotherapeutic applications. A novel molecule, 2-(2-(4-(4-123 Iiodobenzyl)piperazin-1-yl)-2-oxoethyl)isoindoline-1,3-dione (MEL037), was synthesized, labeled with 123 I, and evaluated for application in melanoma tumor scintigraphy and radiotherapy. Methods: The tumor imaging potential of 123 I-MEL037 was studied in vivo in C57BL/6J female mice bearing the B16F0 murine melanoma tumor and in BALB/c nude mice bearing the A375 human amelanotic melanoma tumor by biodistribution, competition studies, and SPECT. Results: 123 I-MEL037 exhibited high and rapid uptake in the B16F0 melanoma tumor at 1 h (13 %ID/g [percentage injected dose per gram]), increasing with time to reach 25 %ID/g at 6 h. A significant uptake was also observed in the eyes (2 %ID, at 3-6 h after injection) of black mice. No uptake was observed in the tumor or in the eyes of nude mice bearing the A375 tumor. Because of high uptake and long retention in the tumor and rapid body clearance, the mean contrast ratios (MCR) of 123 I-MEL037 were 30 and 60, at 24 and 48 h after injection, respectively. At 24 h after injection of mice bearing the B16 melanoma, SPECT indicated that the radioactivity was located predominately in the tumor followed by the eyes, whereas no specific localization of the radioactivity was noted in mice bearing the A375 human amelanotic tumor. In competition experiments, uptake of 123 I-MEL037 in brain, lung, heart, and kidney-organs known to contain s-receptors-was not significantly different in haloperidol-treated animals compared with control animals. Therefore, reduction of uptake in tumor and eyes of the pigmented mice bearing the B16F0 tumor suggested that the mechanism of tumor uptake was likely due to an interaction with melanin. Conclusion: These findings suggested that 123 I-MEL037, which displays a rapid and very high tumor uptake, appeared to be a promising imaging agent for detection of most melanoma tumors with the potential for development as a therapeutic agent in melanoma tumor proliferation.

High-Contrast PET of Melanoma Using 18F-MEL050, a Selective Probe for Melanin with Predominantly Renal Clearance

“…This is likely due to the specific interaction of 18 F-MEL050 with melanin, because no 18 F-MEL050 is retained in these tissues in nonpigmented BALB/c nude mice or in A375 amelanotic tumor grafts. This result is in agreement with previously reported results for 123 I-MEL037, 125 I-BZA, and 125 I-BZA 2 , all exhibiting high affinity for melanin (22,30,31). Moreover, despite a high 125 I-BZA 2 uptake in the eyes of C57BL/6 mice, clinical trials with 123 I-BZA 2 have shown no significant accumulation in human eyes and even demonstrated the feasibility of imaging ocular melanoma with melanin-specific probes (19).…”

“…More recently, a preclinical imaging study by our group demonstrated that a novel iodobenzylpiperazine, 123 I-MEL037, had rapid and 3-fold higher tumor uptake than 123 I-BZA 2 , suggesting a potential for both melanoma imaging and therapeutic applications (22). A preliminary study also reported the synthesis and biodistribution of a PET radiopharmaceutical, N-(2-diethylaminoethyl)-4-18 Ffluorobenzamide (FBZA), showing great promise for PET (23).…”

Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles

“…The cells were maintained in DMEM medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (FBS) (Invitrogen, Carlsbad, CA). B16F10 cells expressing sigma receptors [12] were used as model cells in our study.…”

Synthesis and in Vivo Evaluation of [123I]Melanin-Targeted Agents

“…The four heterocycles chosen are all structural modifications of the piperazine core, known for its stability, 27 to observe what effect this change to stability, flexibility/rigidity would have on the in vivo behavior of the molecules. The synthesis began with the corresponding Boc protected intermediates (26,31,36), which were N-alkylated with either 4-iodo or 4-bromobenzyl bromide to give 27−28, 32−33, and 37−38 followed by Boc-deprotection with TFA and isolation as the free amine as described in Scheme 2.…”