Synthesis and evaluation of novel radioiodinated nicotinamides for malignant melanoma

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.

Keywords: Iodine-123, Iodonicotinamides, Melanoma, B16F0 tumour, A375 tumour, Small animal SPECT