18F-6-Fluoro-N-[2-(diethylamino)ethyl]pyridine-3-carboxamide

Excerpt

The probe ¹⁸F-6-fluoro-N-[2-(diethylamino)ethyl]pyridine-3-carboxamide, abbreviated as ¹⁸F-MEL050, was synthesized by Denoyer et al. for use with melanin-targeted positron emission tomography (PET) of melanoma and its metastasis (1, 2).

Melanoma is a highly malignant tumor that originates in melanocytes. The patient’s outcome is highly dependent on the early detection of metastasis and on the accuracy of staging. Currently, PET with 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) is routinely used for the staging of melanoma, especially for patients with visceral, deep soft tissue, and lymph node metastases (3). However, [¹⁸F]FDG PET suffers from poor sensitivity for the assessment of early stage and small melanomas because of its dependence on glucose metabolism of tumor cells. Lack of specificity of [¹⁸F]FDG also makes it difficult to discriminate lymph node metastasis and inflammatory lymphadenopathy (1, 2). In recent years, several other radiolabeled imaging probes have been evaluated for melanoma imaging by targeting melanoma-associated antigens, α-melanocyte–stimulating hormones, and melanin. Of these probes, benzamide (BZ) derivatives are one group of the most promising radiotracers for both diagnosis and therapeutic applications (4, 5).

BZ derivatives represent a versatile class of aromatic compounds that exhibit high and specific binding with melanin in melanoma cells and melanocytes (6, 7). Clinical trials with the agents of [¹²³I]BZA and [¹²³I]BZA2 have demonstrated the high sensitivity and selectivity of these agents in the detection of melanoma and its metastasis (8-10). Because of the promising results, a large series of BZ derivatives are currently under investigation in animal models of melanoma. In general, these agents exhibit comparable in vitro properties, but they present different kinetic profiles in vivo. Most BZ derivatives exhibit significant liver retention and a predominant clearance via the hepatobiliary system, which potentially limits detection of abdominal lesions (1, 11).

Denoyer et al. synthesized a series of fluoronicotinamide compounds (1, 2, 11). The enhanced hydrophilicity of the pyridine nitrogen allows for rapid clearance of the compounds via renal excretion. The nicotinamide structure is amenable to direct nucleophilic substitution via a rapid, one-step synthesis that provides a means for high-yield incorporation of the ¹⁸F into these molecules. These ¹⁸F-labeled compounds, including ¹⁸F-MEL050, exhibited high radiochemical stability, excellent tumor uptake, and favorable pharmacokinetic properties with excretion predominantly via the renal route (1, 2, 11). These positive characteristics suggest that these agents are potentially valuable as PET agents for early detection of melanoma and its metastasis.

This chapter summarizes the data obtained with ¹⁸F-MEL050 (1, 2).