Preparation and evaluation of ^99mTc-labeled dimeric Tyr³-Octreotide in the AR42J tumor model

Objectives There is an increasing interest in the development of radiolabeled multivalent ligands due to the higher tumor uptake than the corresponding monomer. This report presents the synthesis of a Tyr³-Octreotide dimer conjugate, HYNIC-E[Tyr³-Octreotide]₂ (HYNIC-TOC₂), and the biological evaluation in the AR42J tumor model.

Methods NH₂-E[Tyr³-Octreotide]₂ was synthesized and conjugated with a bifunctional chelator HYNIC. The binding affinity of HYNIC-TOC₂ to SSTR2 was determined in the AR42J rat pancreatic cancer cells, using ¹²⁵I-Tyr³-octreotide as the radiotracer. ^99mTc-HYNIC-TOC₂ was prepared by using tricine and EDDA as coligands. The biodistribution and γ imaging were performed in nude mice bearing AR42J tumors.

Results ^99mTc-HYNIC-TOC₂ was obtained with > 95% labeling yield and favorable stability. Compared with ^99mTc-HYNIC-TOC, ^99mTc-HYNIC-TOC₂ showed significantly increased tumor uptake (13.31 ± 3.14 %ID/g vs 5.32 ± 0.94 %ID/g, 12.05 ± 2.92% ID/g vs 5.01 ± 1.15 %ID/g at 1 h and 4 h p.i., respectively). Although the accumulation of ^99mTc-HYNIC-TOC₂ in kidneys was also significantly increased (94.40 ± 6.51 %ID/g vs 32.27 ± 4.51 %ID/g at 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 at 1 h p.i.). In vivo planar γ imaging showed that the tumors were clearly visualized, while the background signal was much lower except for the kidneys and bladder.

Conclusions These data merit the translation of ^99mTc-HYNIC-TOC₂ to clinical setting. The higher tumor uptake of ^99mTc-HYNIC-TOC₂ suggests that ⁹⁰Y/¹⁷⁷Lu-labeled TOC₂ might have advantage for the radiotherapy of SSTR2- positive tumors.

Research Support NSFC projects (30870728, 30930030, 30900373, and 81000625), an “863” project (2007AA02Z467), a “973” project (2011CB707703), and grants from the Ministry of Science and Technology of China (2009ZX09103-733, 2009ZX09301-010 and 2009ZX09103-746)