Radioiodinated N-(2-diethylaminoethyl)benzamide derivatives with high melanoma uptake:: Structure-affinity relationships, metabolic fate, and intracellular localization
Radioiodinated N-(2-diethylaminoethyl)benzamide derivatives with high melanoma uptake:: Structure-affinity relationships, metabolic fate, and intracellular localization
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DOI：
10.1021/jm991079p
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发表时间：
2000-10-19
影响因子：
7.3
通讯作者：
Haberkorn, U
中科院分区：
文献类型：
--
作者：
Eisenhut, M;Hull, WE;Haberkorn, U
几种放射性碘标记的N-（二烷基氨基烷基）苯甲酰胺已被用于黑色素瘤转移的平面放射成像和单光子发射计算机断层扫描（SPECT）。为了寻求改善黑色素瘤吸收和组织选择性，使用携带B16黑色素瘤的C57 Bl/6小鼠对具有不同苯基取代基的N-（2-二乙氨基乙基）苯甲酰胺进行了结构-活性研究。化合物2（4-氨基-5-溴-N-（2-二乙基氨基乙基）-3-[I-131]碘-2-甲氧基苯甲酰胺）和化合物6（4-乙酰胺基-N-（2-二乙基氨基乙基）-5-[I-131]碘-2-甲氧基苯甲酰胺）在静脉注射后6小时显示例如黑素瘤摄取分别为16.6和23.2%ID/g（平均值，n = 3）。吸收率比文献中已知的苯甲酰胺观察到的高3-5倍（P < 0.01），并且可能是由于2或6相对缓慢的尿液排泄而促进的。相比之下，类似物缺乏MeO，Ac，AcNH，或Br取代基表现出降低肿瘤摄取和高尿排泄的各种苯甲酰胺代谢产物的放射性。B16黑色素瘤中放射性碘化苯甲酰胺的摄取不是由特定机制介导的，如受体结合。2和6显示出相似的黑色素瘤摄取值，但σ（1）-受体亲和力完全不同，分别为Ki = 0.278 +/- 0.018和5.19 +/- 0.40 μ M。IMBA（N-（2-二乙基氨基乙基）-3-[I-131]-碘-4-甲氧基苯甲酰胺）或BZA（N-（2-二乙基氨基乙基）-4-[I-131]碘苯甲酰胺）的摄取研究表明，随着未标记化合物剂量的增加，测量的标记摄取不变（IMBA）甚至增强（BZA），而标记的受体结合减少。差分和平衡密度梯度离心显示，大部分的标记IMBA的放射性与含有黑色素颗粒的馏分。因此，结构-活性研究表明，血液清除率和代谢稳定性是黑色素瘤中苯甲酰胺摄取的主要决定因素。6的高摄取和缓慢清除为患者的黑色素瘤成像提供了相当大的潜力，并且该化合物也可能被证明可用于放射性核素治疗。
Several radioiodinated N-(dialkylaminoalkyl)benzamides have been used for planar scintigraphy and single-photon emission computed tomography (SPECT) of melanoma metastases. In a quest for improved melanoma uptake and tissue selectivity, structure-activity studies for N-(2-diethylaminoethyl)benzamides with variation of phenyl substituents were performed using C57Bl/6 mice bearing B16 melanoma. Compounds 2 (4-amino-5-bromo-N-(2-diethylaminoethyl)-3-[I-131]iodo-2-methoxybenzamide) and 6 (4-acetamido-N-(2-diethylaminoethyl)-5-[I-131]iodo-2-methoxybenzamide) showed at 6 h post iv injection, for example, melanoma uptake of 16.6 and 23.2% ID/g, respectively (mean values, n = 3). Uptake was 3-5 times higher (P < 0.01) than observed with benzamides known from the literature and was probably facilitated by the relatively slow urinary excretion of 2 or 6. In contrast, analogues lacking either the MeO, Ac, AcNH, or Br substituents exhibited reduced tumor uptake and high urinary excretion of radioactivity in various benzamide metabolites. Uptake of radioiodinated benzamides in B16 melanoma is not mediated by a specific mechanism such as -receptor binding. 2 and 6 exhibited similar melanoma uptake values but quite different sigma (1)-receptor affinities of K-i = 0.278 +/- 0.018 and 5.19 +/- 0.40 muM, respectively. Uptake studies with IMBA (N-(2-diethylaminoethyl)-3-[I-131]-iodo-4-methoxybenzamide) or BZA (N-(2-diethylaminoethyl)-4-[I-131]iodobenzamide) showed that with increasing dose of unlabeled compound the measured uptake of label was unchanged (IMBA) or even enhanced (BZA) while receptor binding of label decreased. Differential and equilibrium density-gradient centrifugation revealed that most of the radioactivity from labeled IMBA was associated with fractions containing melanin granules. Thus, structure-activity studies indicate that blood clearance rates and metabolic stability are the main determinants for benzamide uptake in melanoma. The high uptake and slow clearance of 6 offer considerable potential for melanoma imaging in patients, and this compound may also prove to be useful for radionuclide therapy.