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 [Tyr3]octreotide dimer conjugate, HYNIC-E([Tyr3]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 125I- [Tyr3]octreotide as the radiotracer. 99mTc-HYNIC-TOC 2 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. 99mTc-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 99mTc-HYNIC-TOC 2 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 99mTc-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 99mTc-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 99mTc-HYNIC-TOC 2 with a higher binding affinity and good stability was designed and evaluated. The higher tumor uptake of 99mTc-HYNIC-TOC2 suggests that 90Y/177Lu-labeled TOC2 might have an advantage for the radiotherapy of SSTR2-positive tumors. These data merit the translation of 99mTc-HYNIC-TOC2 to a clinical setting.
Original language | English (US) |
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Pages (from-to) | 2925-2933 |
Number of pages | 9 |
Journal | Molecular Pharmaceutics |
Volume | 10 |
Issue number | 8 |
DOIs | |
State | Published - Aug 5 2013 |
Externally published | Yes |
Keywords
- Tc
- [Tyr]octreotide
- dimer
- SPECT
- SSTR2-positive tumor
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery