Background

[PubMed]

Radioiodinated N-[2-[N-ethyl-N-[2-(2-fluoropyridin-3-yloxy)ethyl]amino]ethyl]-6-iodoquinoxaline-2-carboxamide dihydrochloride salt, abbreviated as [¹²⁵I]56, 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 metastases (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 the 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 [¹²⁵I]56 (1).

Synthesis

[PubMed]

Maisonial et al. described the chemical synthesis and characterization of compound 56 in detail (1). Compound 56 was synthesized starting from the corresponding stannane precursor 76 (N-[2-[N-ethyl-N-[2-(2-fluoropyridin-3-yloxy)ethyl]amino]ethyl]-6-tributylstannylquinoxaline-2-carboxamide). The formula of compound 56 was C₂₀H₂₁FIN₅O₂,2HCl,H₂O. The chemical yield was 91%. Radiolabeled versions of compound 56, [¹²⁵I]56 and [¹³¹I]56, were synthesized with a classic electrophilic radioiodo-demetalation reaction, using no-carrier-added [¹²⁵I]NaI and [¹³¹I]NaI, respectively, in acidic medium (citrate buffer) in the presence of chloramine-T monohydrate. The radiochemical yield and purity of [¹²⁵I]56 were 53% and 99.7%, respectively, and the specific activity was 31.9 GBq/μmol (0.86 Ci/µmol). [¹³¹I]56 was obtained with a specific activity of 106.9 GBq/μmol (2.89 Ci/µmol) and a radiochemical purity of 98.5%; the radiochemical yield of [¹³¹I]56 was not reported.

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.

Animal Studies

Human Studies

[PubMed]

No references are currently available.

References

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2.

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