Radiolabeled high affinity peptidomimetic antagonist selectively targets αvβ3 receptor-positive tumor in mice

Jang, Beom-Su; Lim, Esther; Hee Park, Seung; Shin, In Soo; Danthi, S. Narasimhan; Hwang, In Sook; Le, Nhat; Yu, Sarah; Xie, Jianwu; Li, King C.P.; Carrasquillo, Jorge A.; Paik, Chang H.

doi:10.1016/j.nucmedbio.2007.02.002

« Previous Next »Nuclear Medicine and Biology
Volume 34, Issue 4 , Pages 363-370, May 2007

Radiolabeled high affinity peptidomimetic antagonist selectively targets α_vβ₃ receptor-positive tumor in mice

Beom-Su Jang
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Esther Lim
- Department of Radiology, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Seung Hee Park
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
In Soo Shin
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
S. Narasimhan Danthi
- Department of Radiology, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
In Sook Hwang
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Nhat Le
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Sarah Yu
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
Jianwu Xie
- Department of Radiology, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
King C.P. Li
- Department of Radiology, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
- Current address: Department of Radiology, The Methodist Hospital, 6565 Fannin Street, MB1-066 Houston, TX 77030, USA.
Jorge A. Carrasquillo
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
- Current address: Nuclear Medicine Service, Memorial Sloan-Kettering Cancer Center, Mailbox 77, 1275 York Avenue, New York, NY 10021, USA.
Chang H. Paik
- Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
- Corresponding author: Tel.: +1 301 496 1426; fax: +1 301 402 4548.

Received 8 November 2006; received in revised form 8 February 2007; accepted 11 February 2007.

Abstract

Objectives

The aim of this research was to synthesize radiolabeled peptidomimetic integrin α_vβ₃ antagonists that selectively target integrin α_vβ₃ receptor and clear rapidly from the whole body.

Methods

Integrin α_vβ₃ antagonists, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-β-alanine (IA) and 4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-β-alanine hydrochloride (IAC), a hydrophobic carbamate derivative of IA, were conjugated with 2-p-isothiocyanatobenzyl-DOTA at the amino terminus and labeled with ¹¹¹In. The ¹¹¹In labeled IA and IAC were subjected to in vitro receptor binding, biodistribution and imaging studies using nude mice bearing the receptor-positive M21 human melanoma xenografts.

Results

The ¹¹¹In-labeled IA (40%) and -IAC (72%) specifically bound in vitro to α_vβ₃ (0.8 μM) at a molar excess. This receptor binding was completely blocked by a molar excess of cold IA to α_vβ₃. The higher receptor-binding affinity of the ¹¹¹In-labeled IAC was reflected in higher tumor uptake and retention: 5.6±1.4 and 4.5±0.7 %ID/g vs. 3.8±0.9 and 2.0±0.3 %ID/g for the ¹¹¹In-labeled IA at 0.33 and 2 h. The tumor uptakes were inhibited by the co-injection of 200 μg of IA, indicating that the uptake was receptor mediated. These antagonists were excreted primarily via the renal system. The ¹¹¹In activity retained in the whole body was quite comparable between the ¹¹¹In-labeled IA (24% ID) and the ¹¹¹In-labeled IAC (33% ID) at 2 h. The higher peak tumor uptake and longer retention resulted in higher tumor-to-background ratios for the ¹¹¹In-labeled IAC at 2 h with 9.7, 2.3, 0.8, 1.9, 7.1, 2.2, 0.9, 3.7 and 9.9 for blood, liver, kidney, lung, heart, stomach, intestine, bone and muscle, respectively. The imaging studies with the ¹¹¹In-labeled IAC also clearly visualized the receptor-positive tumor at 4 h.

Conclusions

The ¹¹¹In-labeled IAC showed an improve tumor targeting kinetics with rapid accumulation and prolonged retention in the α_vβ₃ receptor-positive tumor. This together with the rapid whole-body clearance pharmacokinetics warrants further studies on this IAC analog for molecular imaging of tumor-induced angiogenic vessels and various malignant human tumors expressing the receptor.

Keywords: Peptidomimetic α_vβ₃ antagonists, In-111 labels, α_vβ₃-mediated tumor uptake