2-(2-(4-(4-[I]Iodobenzyl)piperazin-1-yl)-2-oxoethyl)isoindoline-1,3-dione

2-(2-(4-(4-[I]Iodobenzyl)piperazin-1-yl)-2-oxoethyl)isoindoline-1,3-dione ([I]MEL037) is a radioligand that has been developed as a single-photon emission computed tomography (SPECT) imaging probe for malignant melanoma (1). [I]MEL037 is a radioiodinated benzamide (BZA) labeled with I, a gamma emitter with a physical half-life () of 13.2 h. Malignant melanoma is the sixth most common cancer in the United States (2). Early diagnosis and prompt surgical removal comprise the best approach for a possible cure (3). Melanomas develop from activated or genetically altered neoplastic melanocytes that contain melanin (4-6). Melanin pigment is synthesized and deposited within melanosomes (7). The complex biosynthetic pathway of melanogenesis is catalytically controlled by three gene-related metalloenzymes: tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2 (6). Eumelanin and pheomelanin are the two major types of melanin. Eumelanin is the predominant melanin pigment found in primary tumors. Pheomelanin tends to associate with progression of the disease. Melanins are complex, negatively charged molecules with hydrophobic surfaces, and they have the capability to bind many different types of compounds (4). Because of these properties, melanins represent a very attractive target for both diagnosis and treatment. BZA derivatives and iodobenzamides have been found to have affinity for melanomas (1, 4, 8, 9). The exact mechanisms of uptake of this class of compound have not been fully established (1, 10, 11). Direct melanin binding, involvement in the melanin biosynthesis pathway, and sigma (σ) receptor mediation have been proposed as the most likely mechanisms for different derivatives. In addition, available vascular concentrations of these compounds and their ability to transport into the melanoma cells also influence their cellular uptake (11). Melanin-targeting radiopharmaceuticals that are based on BZA such as [I]BZA, [I]BZA, and [I]IBZM have been investigated and developed for molecular imaging of malignant melanomas (12-14). To produce a radioiodinated BZA analog with higher tumor uptake and faster body clearance, Pham et al. (1, 15) designed and prepared [I]MEL037, which has a piperidine moiety and rigidification of the structure by using an isoindoline-1,3-dione as the backbone. This iodobenzylpiperazine derivative also has a methylene-carbonyl unit and iodine incorporated in the benzylamine instead of the benzamide. Their study showed that [I]MEL037 has a high selective uptake in the murine B16F0 melanotic tumor, and the uptake was most likely related to melanin binding and not to σ receptor binding.