Lewis J S, Srinivasan A, Schmidt M A, Anderson C J
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Nucl Med Biol. 1999 Apr;26(3):267-73. doi: 10.1016/s0969-8051(98)00105-x.
Radiolabeled somatostatin analogs have demonstrated potential as cancer therapeutic agents. Many of these agents are based on the analog octreotide (OC). Recently it has been shown that substitution of a tyrosine for phenylalanine in the 3-position and changing the C-terminus from an alcohol to an acid improves the targeting of somatostatin-rich tissues. The compound, 1,4,8,11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid-Tyr3-octreotate (TETA-Y3-TATE), was synthesized and radiolabeled with 64Cu. The receptor binding properties of 64Cu-TETA-Y3-TATE showed an estimated Kd value of 549 pM in somatostatin receptor-positive CA20948 tissue membrane. High tumor uptake was observed in two animal tumor models. Tumor uptakes of 2.37 %ID/g in CA20948 tumor-bearing rats and 21.60 %ID/g in AR42J tumor-bearing SCID mice were observed at 1 h, compared with 1.09 %ID/g and 11.24 %ID/g for 64Cu-TETA-OC. Higher uptake in other somatostatin-receptor rich tissues was also observed, compared with 64Cu-TETA-OC. Positron emission tomography (PET) imaging with 64Cu-TETA-Y3-TATE in a baboon showed significant uptake in the pituitary and adrenals, and clearance through the kidneys. 64Cu-TETA-Y3-TATE, a new OC analog for binding somatostatin receptors, demonstrated significantly greater uptake in somatostatin-rich tissues in two tumor-bearing animal models, and demonstrated great potential as a radiopharmaceutical for imaging and therapy of somatostatin receptor-positive tissues.
放射性标记的生长抑素类似物已显示出作为癌症治疗药物的潜力。这些药物中的许多都基于类似物奥曲肽(OC)。最近研究表明,在3位用酪氨酸取代苯丙氨酸并将C末端从醇基改为酸基可改善对富含生长抑素组织的靶向性。合成了化合物1,4,8,11-四氮杂环十四烷-N,N',N",N"'-四乙酸-Tyr3-奥曲肽(TETA-Y3-TATE)并用64Cu进行放射性标记。64Cu-TETA-Y3-TATE的受体结合特性显示,在生长抑素受体阳性的CA20948组织膜中,估计的Kd值为549 pM。在两种动物肿瘤模型中观察到高肿瘤摄取。在1小时时,荷CA20948肿瘤大鼠的肿瘤摄取为2.37 %ID/g,荷AR42J肿瘤的SCID小鼠为21.60 %ID/g,相比之下,64Cu-TETA-OC分别为1.09 %ID/g和11.24 %ID/g。与64Cu-TETA-OC相比,在其他富含生长抑素受体的组织中也观察到更高的摄取。用64Cu-TETA-Y3-TATE对狒狒进行正电子发射断层扫描(PET)成像显示,垂体和肾上腺有明显摄取,并通过肾脏清除。64Cu-TETA-Y3-TATE是一种用于结合生长抑素受体的新型OC类似物,在两种荷瘤动物模型中,在富含生长抑素的组织中摄取明显更高,并显示出作为生长抑素受体阳性组织成像和治疗的放射性药物的巨大潜力。