Study on 188Re(I)-Tricarbonyl Labeled His3-Octreotide as an Imaging and Therapeutic Agent for Pancreas Tumor

• Main Authors: Cheng, Yu-En, 鄭宇恩
• Other Authors: Lo, Jem-Mau
• Format: Others
• Language: en_US
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/84919533020471479555

碩士 === 國立清華大學 === 生醫工程與環境科學系 === 97 === Octreotide, a somatostatin analogue, is consisted of eight amino acids as a cyclic octapeptide and has a high binding affinity to somatostatin receptor 2 (sst2). Recently, systematic receptor-targeted or metabolically directed radiotherapy using various radioisotopes for therapy of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has aroused extensive interest in nuclear medicine. [90Y-DOTA0-Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are currently clinically used for GEP-NETs therapy. However, they may cause high radiation dose in kidney or bone marrow. The aim of this study was to develop a novel radiolabeled octreotide analogue, 188Re(I)-his3-octreotide, as an imaging and therapeutic agent for neuroendocrine tumors. Methods：First, octreotide was conjugated with three histidines, referred to his3-octreotide, by a solid phase peptide synthesizer. Binding affinity of his3-octreotide for sst2 was measured by competitive binding assay. Then, [188Re(OH2)3(CO)3]+ was prepared as a precursor and labeled directly to his3-octreotide. The resultant solution containing 188Re(I)-his3-octreotide was measured for its radiochemical purity by high performance liquid chromatography (HPLC) and purified by C18 Sep-Pak cartridge. In vitro stability and in vivo targeting in AR42J-bearing mice were assessed. Results：In competitive binding assay, his3-octreotide showed high affinity for sst2 and IC50 value was similar to the value of octreotide. The radiochemical purity of [188Re(OH2)3(CO)3]+ reached about 85 %. The radiochemical purity of purified 188Re(I)-his3-octreotide achieved greater than 95 %. In stability test, the stability of 188Re(I)-his3-octreotide decreased to 60 % in saline at 48 h post-injection. However, in human serum and rat serum, the stability of 188Re(I)-his3-octreotide decreased to 50 % and 10 %, respectively at 48 h post-injection. In biodistribution study, it was indicated that 188Re(I)-his3-octreotide had high accumulations in liver, kidneys, and spleen. In microSPECT/CT imaging, the AR42J tumor in the SCID mouse could be slightly visualized at 1 and 4 h postinjection. The AR42J tumor uptake of 188Re(I)-his3-octreotide was blocked completely in the case of additional administration of a large excess amount (100 μg) of unlabeled his3-octreotide. Conclusion：From the work, it is evident from the in vivo study that his3-octreotide exhibits a high affinity for sst2. However, the accumulation of the 188Re(I) labeled peptide in AR42J tumor in the animal was slightly displayed within 4 h post-injection but become dim later. The poor uptake in the tumor might be due to the unstability of the agent in blood. If 188Re(I)-his3-octreotide could be modified further to be 188Re(I)-his6-octreotide, the new designed 188Re(I) labeled octreotide would become stable and worthy to be developed as an imaging and therapeutic agent for GEP-NETs.