Aloj L, Panico M, Caraco C, Del Vecchio S, Arra C, Affuso A, Accardo A, Mansi R, Tesauro D, De Luca S, Pedone C, Visentin R, Mazzi U, Morelli G, Salvatore M
Istituto di Biostrutture e Bioimmagini, CNR, Napoli, Italy.
Cancer Biother Radiopharm. 2004 Feb;19(1):93-8. doi: 10.1089/108497804773391739.
Cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with 111In or 99mTc for CCK-B receptor imaging. Derivatives of CCK8 were obtained by addition at the N-terminus in solid phase of a DTPA derivative (DTPAGlu) linked through a glycine spacer (DTPAGlu-G-CCK8) or cysteine, glycine and a diphenylphosphinopropionyl moiety (PhosGC-CCK8) for labeling with 111In and 99mTc, respectively. CCK-BR overexpressing A431 cancer cell lines were utilized to characterize in vitro properties of the two compounds as well as for generating xenografts in nude mice for in vivo characterization. Both 111In-DTPAGlu-G-CCK8 and 99mTcPhosGC-CCK8 showed similar binding affinities for CCK-BR with dissociation constants of 20-40 nM, were internalized after interaction with the receptor and displayed prolonged cellular retention times. Specific in vivo interaction with the receptor of both CCK8 analogs was observed in our animal model. 111In-DTPAGlu-G-CCK8 showed better target to non-target ratios, although it appeared to be rapidly metabolized after injection and activity cleared through the kidneys. 99mTc-PhosGC-CCK8 was more stable in vivo but showed marked hepatobiliary clearance with resulting high background activity in the bowel. The rapid clearance and lower background obtained with 111In-DTPAGlu-G-CCK8 make this a better candidate for further development.
已证明B亚型胆囊收缩素（CCK）受体（CCK-BR）在包括甲状腺髓样癌在内的某些神经内分泌肿瘤中过表达。我们最近的工作集中在使用111In或99mTc对CCK8肽进行放射性标记以用于CCK-B受体成像的新方法上。CCK8的衍生物是通过在固相中将通过甘氨酸间隔基连接的DTPA衍生物（DTPAGlu）（DTPAGlu-G-CCK8）或半胱氨酸、甘氨酸和二苯基膦酰丙酰基部分（PhosGC-CCK8）添加到N端获得的，分别用于用111In和99mTc进行标记。利用过表达CCK-BR的A431癌细胞系来表征这两种化合物的体外特性，并在裸鼠中生成异种移植物用于体内表征。111In-DTPAGlu-G-CCK8和99mTc-PhosGC-CCK8对CCK-BR显示出相似的结合亲和力，解离常数为20-40 nM，与受体相互作用后被内化，并显示出延长的细胞保留时间。在我们的动物模型中观察到两种CCK8类似物与受体的特异性体内相互作用。111In-DTPAGlu-G-CCK8显示出更好的靶标与非靶标比率，尽管它在注射后似乎迅速代谢，并且活性通过肾脏清除。99mTc-PhosGC-CCK8在体内更稳定，但显示出明显的肝胆清除，导致肠道背景活性较高。111In-DTPAGlu-G-CCK8的快速清除和较低背景使其成为进一步开发的更好候选物。
