De Jong M, Bakker W H, Breeman W A, Bernard B F, Hofland L J, Visser T J, Srinivasan A, Schmidt M, Béhé M, Mäcke H R, Krenning E P
Department of Nuclear Medicine, University Hospital Dijkzigt, Rotterdam, The Netherlands.
Int J Cancer. 1998 Jan 30;75(3):406-11. doi: 10.1002/(sici)1097-0215(19980130)75:3<406::aid-ijc14>3.0.co;2-6.
We have evaluated the potential usefulness of radiolabelled [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide as radiopharmaceuticals for somatostatin receptor-targeted scintigraphy and radiotherapy. In vitro somatostatin receptor binding and in vivo metabolism in rats of the compounds were investigated in comparison with [111In-DTPA0] octreotide. Comparing different peptide-chelator constructs, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide were found to have a higher affinity than [DTPA0]octreotide for subtype 2 somatostatin receptors (sst2) in mouse AtT20 pituitary tumour cell membranes (all IC50 values obtained were in the low nanomolar range). In vivo studies in CA20948 tumor-bearing Lewis rats revealed a significantly higher uptake of both 111In-labelled [DOTA0,Tyr3]octreotide and [DTPA0,Tyr3]octreotide in sst2-expressing tissues than after injection of [111In-DTPA0]octreotide, showing that substitution of Tyr for Phe at position 3 in octreotide results in an increased affinity for its receptor and in a higher target tissue uptake. Uptake of 111In-labelled [DTPA0]octreotide, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide in pituitary, pancreas, adrenals and tumour was decreased to less than 7% of control by pre-treatment with 0.5 mg unlabelled octreotide/rat, indicating specific binding to sst2. Comparing different radionuclides, [90Y-DOTA0,Tyr3]octreotide had the highest uptake in sst2-positive organs, followed by the [111In-DOTA0,Tyr3]octreotide, whereas [DOTA0,125I-Try3]octreotide uptake was low compared to that of the other radiopharmaceuticals, when measured 24 hr after injection. Renal uptake of 111In-labelled [DTPA0]octreotide, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide was reduced over 50% by an i.v. injection of 400 mg/kg D-lysine, whereas radioactivity in blood, pancreas and adrenals was not affected.
我们评估了放射性标记的[DTPA0,Tyr3]奥曲肽和[DOTA0,Tyr3]奥曲肽作为用于生长抑素受体靶向闪烁扫描和放射治疗的放射性药物的潜在效用。与[111In-DTPA0]奥曲肽相比，研究了这些化合物在大鼠体内的体外生长抑素受体结合情况和体内代谢。比较不同的肽-螯合剂构建体，发现[DTPA0,Tyr3]奥曲肽和[DOTA0,Tyr3]奥曲肽在小鼠AtT20垂体肿瘤细胞膜中对2型生长抑素受体（sst2）的亲和力高于[DTPA0]奥曲肽（所有获得的IC50值均在低纳摩尔范围内）。在携带CA20948肿瘤的Lewis大鼠中进行的体内研究表明，与注射[111In-DTPA0]奥曲肽后相比，111In标记的[DOTA0,Tyr3]奥曲肽和[DTPA0,Tyr3]奥曲肽在表达sst2的组织中的摄取均显著更高，这表明奥曲肽3位的酪氨酸被苯丙氨酸取代后，其对受体的亲和力增加，且靶组织摄取更高。用0.5 mg未标记的奥曲肽/大鼠预处理后，垂体、胰腺、肾上腺和肿瘤中111In标记的[DTPA0]奥曲肽、[DTPA0,Tyr3]奥曲肽和[DOTA0,Tyr3]奥曲肽的摄取降至对照的7%以下，表明与sst2特异性结合。比较不同的放射性核素，注射后24小时测量时，[90Y-DOTA0,Tyr3]奥曲肽在sst2阳性器官中的摄取最高，其次是[111In-DOTA0,Tyr3]奥曲肽，而[DOTA0,125I-Try3]奥曲肽的摄取与其他放射性药物相比很低。静脉注射400 mg/kg D-赖氨酸可使111In标记的[DTPA0]奥曲肽、[DTPA0,Tyr3]奥曲肽和[DOTA0,Tyr3]奥曲肽的肾脏摄取降低50%以上，而血液、胰腺和肾上腺中的放射性不受影响。
