(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.

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.