title: (99m)Tc-labeled dimeric octreotide peptide: a radiotracer with high tumor uptake for single-photon emission computed tomography imaging of somatostatin receptor subtype 2-positive tumors.
abstract: There is growing interest in the development of radiolabeled multivalent ligands because of their higher tumor uptake versus that of the corresponding monomer. This report presents the synthesis of a [Tyr(3)]octreotide dimer conjugate, HYNIC-E([Tyr(3)]octreotide)2 {HYNIC-TOC2, HYNIC = 6-[2-(2-sulfonatobenzaldehyde)hydrazono]nicotinyl}, and its biological evaluation in the AR42J tumor model. The binding affinity of HYNIC-TOC2 for somatostatin receptor subtype 2 (SSTR2) was determined in AR42J rat pancreatic cancer cells, using (125)I-[Tyr(3)]octreotide as the radiotracer. (99m)Tc-HYNIC-TOC2 was prepared by using tricine and EDDA as coligands (EDDA = ethylenediamine-N,N'-diacetic acid). Biodistribution and γ imaging were performed in nude mice bearing AR42J tumors. (99m)Tc-HYNIC-TOC2 was obtained in >95% labeling yield with favorable stability. Compared with those of HYNIC-TOC (IC50 = 3.74 ± 0.82 nM), HYNIC-TOC2 showed significantly increased SSTR2 binding affinity (IC50 = 0.74 ± 0.19 nM), and (99m)Tc-HYNIC-TOC2 showed significantly increased tumor uptake [13.31 ± 3.14%ID/g vs 5.32 ± 0.94%ID/g 1 h postinjection (p.i.) and 12.05 ± 2.92%ID/g vs 5.87 ± 1.96%ID/g 4 h p.i.]. Although the level of accumulation of (99m)Tc-HYNIC-TOC2 in kidneys was significantly increased (94.40 ± 6.51%ID/g vs 32.27 ± 4.51%ID/g 1 h p.i.), this high uptake was inhibited by the injection of l-lysine before the administration of (99m)Tc-HYNIC-TOC2 (30.99 ± 5.05%ID/g 1 h p.i.) while tumor uptake decreased only slightly. Consistent with biodistribution data, in vivo planar γ imaging showed that the tumors were clearly visualized, while the background signal was much weaker except for that of the kidneys and bladder. The new radiotracer (99m)Tc-HYNIC-TOC2 with a higher binding affinity and good stability was designed and evaluated. The higher tumor uptake of (99m)Tc-HYNIC-TOC2 suggests that (90)Y/(177)Lu-labeled TOC2 might have an advantage for the radiotherapy of SSTR2-positive tumors. These data merit the translation of (99m)Tc-HYNIC-TOC2 to a clinical setting.
authors.affiliation: Medical Isotopes Research Center, Peking University , Beijing 100191, China.
authors.forename: Chengyan
authors.initials: C
authors.lastname: Dong
authors.forename: Huiyun
authors.initials: H
authors.lastname: Zhao
authors.forename: Sujuan
authors.initials: S
authors.lastname: Yang
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.forename: Jinming
authors.initials: J
authors.lastname: Huang
authors.forename: Liyang
authors.initials: L
authors.lastname: Cui
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhong
authors.forename: Xiaona
authors.initials: X
authors.lastname: Jin
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D005260:Female; D051379:Mice; D008819:Mice, Nude; D015282:Octreotide / Q000737:chemistry*; D015609:Organotechnetium Compounds / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000175:diagnosis; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D015609:Organotechnetium Compounds; D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2; D015282:Octreotide