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.