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Radiolabeled high affinity peptidomimetic antagonist selectively targets alpha(v)beta(3) receptor-positive tumor in
Beom-Su Jang1, Esther Lim, Seung Hee Park
1Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Objectives:
The aim of this research was to synthesize radiolabeled peptidomimetic integrin alpha(v)beta(3) antagonists that selectively target integrin alpha(v)beta(3) receptor and clear rapidly from the whole body.
Methods:
Integrin alpha(v)beta(3) antagonists, 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-beta-alanine (IA) and 4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-beta-alanine hydrochloride (IAC), a hydrophobic carbamate derivative of IA, were conjugated with 2-p-isothiocyanatobenzyl-DOTA at the amino terminus and labeled with (111)In. The (111)In 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 (111)In-labeled IA (40%) and -IAC (72%) specifically bound in vitro to alpha(v)beta(3) (0.8 microM) at a molar excess. This receptor binding was completely blocked by a molar excess of cold IA to alpha(v)beta(3). The higher receptor-binding affinity of the (111)In-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 (111)In-labeled IA at 0.33 and 2 h. The tumor uptakes were inhibited by the co-injection of 200 microg of IA, indicating that the uptake was receptor mediated. These antagonists were excreted primarily via the renal system. The (111)In activity retained in the whole body was quite comparable between the (111)In-labeled IA (24% ID) and the (111)In-labeled IAC (33% ID) at 2 h. The higher peak tumor uptake and longer retention resulted in higher tumor-to-background ratios for the (111)In-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 (111)In-labeled IAC also clearly visualized the receptor-positive tumor at 4 h.
Conclusions:
The (111)In-labeled IAC showed an improve tumor targeting kinetics with rapid accumulation and prolonged retention in the alpha(v)beta(3) 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.
Insights
Researchers developed novel radiolabeled integrin alpha(v)beta(3) antagonists, including (111)In-labeled IAC, which demonstrated superior tumor targeting and retention. These agents show promise for molecular imaging of tumors expressing the integrin alpha(v)beta(3) receptor.
Area of Science:
- Radiopharmaceutical chemistry
- Molecular imaging
- Oncology
Background:
- Integrin alpha(v)beta(3) is a key biomarker for tumor angiogenesis and progression.
- Development of targeted radiotracers is crucial for accurate cancer diagnosis and monitoring.
Purpose of the Study:
- To synthesize and evaluate novel radiolabeled peptidomimetic integrin alpha(v)beta(3) antagonists.
- To achieve selective targeting of alpha(v)beta(3) receptors with rapid whole-body clearance.
Main Methods:
- Synthesis and radiolabeling of integrin alpha(v)beta(3) antagonists (IA and IAC) with Indium-111.
- In vitro receptor binding assays.
- In vivo biodistribution and imaging studies in nude mice bearing human melanoma xenografts.
Main Results:
- Both (111)In-labeled IA and IAC showed specific binding to alpha(v)beta(3) receptors.
- (111)In-labeled IAC exhibited higher tumor uptake and retention compared to (111)In-labeled IA.
- Rapid renal excretion was observed for both compounds, leading to low whole-body retention at 2 hours post-injection.
Conclusions:
- The (111)In-labeled IAC demonstrated improved tumor targeting kinetics, with rapid accumulation and prolonged retention in alpha(v)beta(3)-positive tumors.
- The favorable pharmacokinetic profile of (111)In-labeled IAC supports its potential for molecular imaging of angiogenic vessels and various human tumors.
- Further studies are warranted to explore the clinical utility of this IAC analog.
