Background

[PubMed]

N-[2-[N-Ethyl-N-[2-(2-[¹⁸F]fluoropyridin-3-yloxy)ethyl]amino]ethyl]-6-iodoquinoxaline-2-carboxamide, abbreviated as [¹⁸F]44, is a quinoxaline benzamide (BZA) derivative that was synthesized for melanin-targeted radionuclide imaging and therapy of melanoma (1).

BZA derivatives represent a versatile class of aromatic compounds that possess a common structure element of Ph-CONH(CH₂)_mNR₂ (m = 1, 2) and exhibit comparable properties, including high and specific binding with melanin in melanoma cells and melanocytes (2-4). Some of these compounds, such as N-(2-diethylaminoethyl)-4-[¹²³I]iodobenzamide ([¹²³I]BZA) and [¹²³I]-N-(2-diethylaminoethyl)-2-iodobenzamide ([¹²³I]BZA2), have been successfully evaluated in melanoma patients, showing high sensitivity and selectivity in the detection of melanoma and its metastasis (5-8).

The promising results with [¹²³I]BZA have prompted great efforts from several groups in screening BZA analogs (2, 9, 10). Among them is a group of investigators in France who synthesized a series of BZA derivatives via structure-activity studies (11, 12). On the basis of the structure of the lead agent [¹²³I]BZA, they synthesized a group of spermidine BZA derivatives by replacing the diethylaminoethyl moiety in the BZA structure with a triamine (spermidine). Spermidine BZA derivatives exhibit high affinity for melanin comparable to that of [¹²³I]BZA; however, these compounds exhibit less accumulation in tumors than [¹²³I]BZA in animal models of melanoma (13). More recently, the investigators generated a class of heteroaromatic BZA analogs by incorporating the heteroaromatic structure in place of the benzene moiety to take advantage of the polycyclic aromatic compounds that display a strong affinity for melanin while keeping the lipophilic side chain (14). The heteroaromatic analogs, [¹²⁵I]5a through [¹²⁵I]5I, showed high specific and long-lasting uptake in the melanoma, which is favorable for combined imaging and therapy. At the same time, the investigators also identified a group of quinoxaline analogs; radioiodinated derivative 3 (ICF01012) is one of these compounds, which show the most favorable pharmacokinetic properties for radionuclide therapy (15, 16). The rapid and specific tumor uptake of quinoxaline compounds also suggests that they are potentially valuable for radionuclide imaging. For radiofluorination, ICF01012 was modified by incorporating 2- or 6-fluoropyridine in the N,N-diethylethylenediamine framework of ICF01012. This strategy allows nucleophilic heteroaromatic radiofluorination of corresponding halogeno- or nitro-precursors without the need for an additional electron-withdrawing substituent in the aromatic ring. Fluoropyridine was introduced on the tertiary amine either directly or in combination with various linkers, which resulted in a group of amide tracers, such as agents [¹²⁵I]56 and [¹⁸F]44 (compound 56 is the dihydrochloride salt of 44) (1). These derivatives showed favorable properties for combined radionuclide imaging (¹⁸F, ¹²⁵I) and therapy (¹³¹I) of melanoma using a single chemical structure. The following is a list of some representative agents that were synthesized and tested by the investigators from the group in France.

BZA derivatives: [^125/123I]BZA, [¹²⁵I]BZA2, [¹²⁵I]BZ18, and [¹²⁵I]5a through [¹²⁵I]5I; and quinoxaline derivatives: [^125/131I]ICF01012 (or [^125/131I]3), [¹²⁵I]56, and [¹⁸F]44.

This chapter summarizes the data of imaging studies obtained with [¹⁸F]44 (1).

Synthesis

[PubMed]

Maisonial et al. prepared [¹⁸F]44 via a three-step, two-pot, radiosynthetic procedure that was automated with a Zymate laboratory automation system. ¹⁸F was incorporated into precursor 75 (tert-butyl N-[2-[N-ethyl-N-[2-(2-nitropyridin-3-yloxy)ethyl]amino]ethyl]carbamate) to give [¹⁸F]74 in yields ranging from 20% to 40%; acidic N-boc deprotection of [¹⁸F]74 generated the radioactive intermediate [¹⁸F]29, and acylation of [¹⁸F]29 to provide [¹⁸F]44 (1). Acylation yields of the conversion of [¹⁸F]29 to [¹⁸F]44 ranged between 20% and 40% (nonisolated decay-corrected yields). The chemical purity was >95%. [¹⁸F]44 could be produced in 6% to 10% nonisolated decay-corrected yields with a specific radioactivity of 0.25–0.34 TBq/μmol (6.76–9.19 Ci/µmol) (calculated from three consecutive high-performance liquid chromatography analyses) in 110−130 min.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro data of the lead compound 3 were summarized in the literature regarding [¹²⁵I]ICF01012 (or [¹²⁵I]3) (15, 16). In vitro studies with cells were not performed for the compound 56 or the agent [¹⁸F]44.

Animal Studies

Human Studies

[PubMed]

No references are currently available.

References

1.

Maisonial A., Kuhnast B., Papon J., Boisgard R., Bayle M., Vidal A., Auzeloux P., Rbah L., Bonnet-Duquennoy M., Miot-Noirault E., Galmier M.J., Borel M., Askienazy S., Dolle F., Tavitian B., Madelmont J.C., Moins N., Chezal J.M. Single photon emission computed tomography/positron emission tomography imaging and targeted radionuclide therapy of melanoma: new multimodal fluorinated and iodinated radiotracers. J Med Chem. 2011;54(8):2745–66. [PubMed: 21417462]

2.

Oltmanns D., Eisenhut M., Mier W., Haberkorn U. Benzamides as melanotropic carriers for radioisotopes, metals, cytotoxic agents and as enzyme inhibitors. Curr Med Chem. 2009;16(17):2086–94. [PubMed: 19519383]

3.

Chehade F., De Labriolle-Vaylet C., Michelot J., Moins N., Moreau M.F., Hindie E., Papon J., Escaig F., Galle P., Veyre A. Distribution of I-BZA (N-2-diethylaminoethyl-4-iodobenzamide) in grafted melanoma and normal skin: a study by secondary ion mass spectroscopy. Cell Mol Biol (Noisy-le-grand). 2001;47(3):529–34. [PubMed: 11441960]

4.

Greguric I., Taylor S.R., Denoyer D., Ballantyne P., Berghofer P., Roselt P., Pham T.Q., Mattner F., Bourdier T., Neels O.C., Dorow D.S., Loc'h C., Hicks R.J., Katsifis A. Discovery of [18F]N-(2-(diethylamino)ethyl)-6-fluoronicotinamide: a melanoma positron emission tomography imaging radiotracer with high tumor to body contrast ratio and rapid renal clearance. J Med Chem. 2009;52(17):5299–302. [PubMed: 19691348]

5.

Bacin F., Michelot J., Bonafous J., Veyre A., Moreau M.F., Kemeny J.L., Chossat F., Bekhechi D. Clinical study of [123I] N-(2-diethylaminoethyl)-4-iodobenzamide in the diagnosis of primary and metastatic ocular melanoma. Acta Ophthalmol Scand. 1998;76(1):56–61. [PubMed: 9541435]

6.

Michelot J.M., Moreau M.F., Veyre A.J., Bonafous J.F., Bacin F.J., Madelmont J.C., Bussiere F., Souteyrand P.A., Mauclaire L.P., Chossat F.M. et al. Phase II scintigraphic clinical trial of malignant melanoma and metastases with iodine-123-N-(2-diethylaminoethyl 4-iodobenzamide). J Nucl Med. 1993;34(8):1260–6. [PubMed: 8326382]

7.

Mansard S., Papon J., Moreau M.F., Miot-Noirault E., Labarre P., Bayle M., Veyre A., Madelmont J.C., Moins N. Uptake in melanoma cells of N-(2-diethylaminoethyl)-2-iodobenzamide (BZA2), an imaging agent for melanoma staging: relation to pigmentation. Nucl Med Biol. 2005;32(5):451–8. [PubMed: 15982575]

8.

Moins N., D'Incan M., Bonafous J., Bacin F., Labarre P., Moreau M.F., Mestas D., Noirault E., Chossat F., Berthommier E., Papon J., Bayle M., Souteyrand P., Madelmont J.C., Veyre A. 123I-N-(2-diethylaminoethyl)-2-iodobenzamide: a potential imaging agent for cutaneous melanoma staging. Eur J Nucl Med Mol Imaging. 2002;29(11):1478–84. [PubMed: 12397467]

9.

Labarre P., Papon J., Moreau M.F., Moins N., Bayle M., Veyre A., Madelmont J.C. Melanin affinity of N-(2-diethylaminoethyl)-4-iodobenzamide, an effective melanoma imaging agent. Melanoma Res. 2002;12(2):115–21. [PubMed: 11930107]

10.

Moins N., Papon J., Seguin H., Gardette D., Moreau M.F., Labarre P., Bayle M., Michelot J., Gramain J.C., Madelmont J.C., Veyre A. Synthesis, characterization and comparative biodistribution study of a new series of p-iodine-125 benzamides as potential melanoma imaging agents. Nucl Med Biol. 2001;28(7):799–808. [PubMed: 11578901]

11.

Desbois N., Gardette M., Papon J., Labarre P., Maisonial A., Auzeloux P., Lartigue C., Bouchon B., Debiton E., Blache Y., Chavignon O., Teulade J.C., Maublant J., Madelmont J.C., Moins N., Chezal J.M. Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma. Bioorg Med Chem. 2008;16(16):7671–90. [PubMed: 18656367]

12.

Labarre P., Papon J., Rose A.H., Guerquin-Kern J.L., Morandeau L., Wu T.D., Moreau M.F., Bayle M., Chezal J.M., Croisy A., Madelmont J.C., Turner H., Moins N. Melanoma affinity in mice and immunosuppressed sheep of [(125)I]N-(4-dipropylaminobutyl)-4-iodobenzamide, a new targeting agent. Nucl Med Biol. 2008;35(7):783–91. [PubMed: 18848663]

13.

Moreau M.F., Papon J., Labarre P., Moins N., Borel M., Bayle M., Bouchon B., Madelmont J.C. Synthesis, in vitro binding and biodistribution in B16 melanoma-bearing mice of new iodine-125 spermidine benzamide derivatives. Nucl Med Biol. 2005;32(4):377–84. [PubMed: 15878507]

14.

Chezal J.M., Papon J., Labarre P., Lartigue C., Galmier M.J., Decombat C., Chavignon O., Maublant J., Teulade J.C., Madelmont J.C., Moins N. Evaluation of radiolabeled (hetero)aromatic analogues of N-(2-diethylaminoethyl)-4-iodobenzamide for imaging and targeted radionuclide therapy of melanoma. J Med Chem. 2008;51(11):3133–44. [PubMed: 18481842]

15.

Bonnet M., Mishellany F., Papon J., Cayre A., Penault-Llorca F., Madelmont J.C., Miot-Noirault E., Chezal J.M., Moins N. Anti-melanoma efficacy of internal radionuclide therapy in relation to melanin target distribution. Pigment Cell Melanoma Res. 2010;23(5):e1–11. [PubMed: 20444199]

16.

Bonnet-Duquennoy M., Papon J., Mishellany F., Labarre P., Guerquin-Kern J.L., Wu T.D., Gardette M., Maublant J., Penault-Llorca F., Miot-Noirault E., Cayre A., Madelmont J.C., Chezal J.M., Moins N. Targeted radionuclide therapy of melanoma: anti-tumoural efficacy studies of a new 131I labelled potential agent. Int J Cancer. 2009;125(3):708–16. [PubMed: 19437532]