Evaluation of Novel In-111-Labeled Gonadotropin-Releasing Hormone Peptides for Human Prostate Cancer Imaging

Objectives We previously reported ¹¹¹In-DOTA-Ahx-D-Phe-(D-Lys⁶-GnRH) as an imaging probe for human prostate cancer. Interestingly, we found that the introduction of D-Phenylalanine (D-Phe) enhanced the receptor binding affinities of gonadotropin-releasing hormone (GnRH) peptides. The aim of this study was to examine whether such favorable effect of D-Phe could be applied to other linkers besides the Ahx linker.

Methods Based upon the structure of DOTA-Ahx-D-Phe-(D-Lys⁶-GnRH), we replaced the Ahx with β-alanine, aminooctanoic acid (Aoc) and aminoundecanoic acid (Aun) separately to generate new DOTA-β-Ala-D-Phe-(D-Lys⁶-GnRH), DOTA-Aoc-D-Phe-(D-Lys⁶-GnRH) and DOTA-Aun-D-Phe-(D-Lys⁶-GnRH). Their GnRH receptor binding affinities were determined using Millipore ChemiScreen^TM human GnRH receptor membrane preparations. The biodistribution and tumor imaging properties of ¹¹¹In-GnRH peptides were determined on DU145 human prostate cancer-xenografted nude mice.

Results DOTA-Aoc-D-Phe-(D-Lys⁶-GnRH) displayed the strongest GnRH binding affinity (6.6 nM), followed by DOTA-β-Ala-D-Phe-(D-Lys⁶-GnRH) (10.7 nM) and DOTA-Aun-D-Phe-(D-Lys⁶-GnRH) (26.3 nM). Furthermore, ¹¹¹In-DOTA-Aoc-D-Phe-(D-Lys⁶-GnRH) showed rapid tumor uptake (1.13 ± 0.36% ID/g at 0.5 h post-injection) coupled with fast whole-body clearance through the urinary system. The DU145 human prostate cancer-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 1 h post-injection of ¹¹¹In-DOTA-Aoc-D-Phe-(D-Lys⁶-GnRH).

Conclusions The successful imaging of DU145 human prostate cancer-xenografted tumor lesions using ¹¹¹In-DOTA-Aoc-D-Phe-(D-Lys⁶-GnRH) highlighted its potential for human prostate cancer imaging.