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The high melanoma uptake and rapid body clearance displayed by our series of [(123)I]iodonicotinamides prompted the development of [(18)F]N-(2-(diethylamino)ethyl)-6-fluoronicotinamide ([(18)F]2), a novel radiotracer for PET melanoma imaging. Significantly, unlike fluorobenzoates, [(18)F]fluorine incorporation on the nicotinamide ring is one step, facile, and high yielding. [(18)F]2 displayed high tumor uptake, rapid body clearance via predominantly renal excretion, and is currently being evaluated in preclinical studies for progression into clinical trials to assess the responsiveness of therapeutic agents.

Unlabelled: 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)I-iodobenzyl)piperazin-1-yl)-2-oxoethyl)isoindoline-1,3-dione (MEL037), was synthesized, labeled with 123I, and evaluated for application in melanoma tumor scintigraphy and radiotherapy., Methods: The tumor imaging potential of 123I-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: 123I-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 123I-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 123I-MEL037 in brain, lung, heart, and kidney--organs known to contain sigma-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 123I-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.

Abstract: Introduction: A series of iodonicotinamides based on the melanin-binding iodobenzamide compound N-2-diethylaminoethyl-4-iodobenzamide was prepared and evaluated for the potential imaging and staging of disseminated metastatic melanoma. Methods: [123I]Iodonicotinamides were prepared by iododestannylation reactions using no-carrier-added iodine-123 and evaluated in vivo by biodistribution and competition studies and by single photon emission computed tomography (SPECT) imaging in black and albino nude mice bearing B16F0 murine melanotic and A375 human amelanotic melanoma tumours, respectively. Results: The iodonicotinamides displayed low-affinity binding for σ1–σ2 receptors (K i>300 nM). In biodistribution studies in mice, N-(2-(diethylamino)ethyl)-5-[123I]iodonicotinamide ([123I]1) exhibited the fastest and highest uptake of the nicotinamide series in the B16F0 tumour at 1 h (∼8% ID/g), decreasing slowly over time. No uptake was observed in the A375 tumour. Clearance from the animals by urinary excretion was more rapid for N-alkyl-nicotinamides than for piperazinyl derivatives. At 1 h postinjection, the urinary excretion was 66% ID for [123I]1, while the gastrointestinal tract amounted to 17% ID. Haloperidol was unable to reduce the uptake of [123I]1 in pigmented mice, indicating that this uptake was likely due to an interaction with melanin. SPECT imaging of [123I]1 in black mice bearing the B16F0 melanoma indicated that the radioactivity was predominately located in the tumour and eyes. No specific localisation was observed in nude mice bearing A375 amelanotic tumours. Conclusion: These findings suggest that [123I]1, which displays high tumour uptake with rapid clearance from the body, could be a promising imaging agent for the detection of melanotic tumours. [Copyright &y& Elsevier]

[18F]6-Fluoro-N-[2-(diethylamino)ethyl]nicotinamide [18F]MEL050 is a novel nicotinamide-based radiotracer, designed to target random metastatic dissemination of melanoma tumours by targeting melanin. Preclinical studies suggest that [18F]MEL050 has an excellent potential to improve diagnosis and staging of melanoma. Here we report the radiochemical optimization conditions of [18F]MEL050 and its large scale automated synthesis using a GE FXFN automated radiosynthesis module for clinical, phase-1 investigation. [18F]MEL050 was prepared via a one-step synthesis using no-carrier added K[18F]F-Krytpofix® 222 (DMSO, 170°C, 5min) followed by HPLC purification. Using 6-chloro-N-[2-(diethylamino)ethyl]nicotinamide as precursor, [18F]MEL050 was obtained in 40–46% radiochemical yield (nondecay corrected), in greater than 99.9% radiochemical purity and specific activity ranging from 240 to 325GBqμmol-1. Total synthesis time including formulation was 40min and [18F]MEL050 was stable (99.8%) in PBS for 6h. [ABSTRACT FROM AUTHOR]