Scholarlink

Background <p>Fibroblast activation protein (FAP) has emerged as a critical biomarker in the tumor microenvironment of various cancers. Radioligands targeting FAP have shown promise for cancer theranostics. To advance cancer imaging, we synthesized a dimeric radioligand based on a 4-quinolinoyl-glycyl-2-cyanopyrrolidine scaffold and conducted studies in cells and mouse tumor models to evaluate its target-binding affinity and PET imaging performance.</p> Results <p>OncoFAP, a commercially available FAP ligand, was conjugated via amide coupling with 1,4-butanediamine to generate a monomeric intermediate, hmFAP<sub>1</sub>. A homodimeric molecule, hmFAP<sub>2</sub>, was synthesized by tethering two hmFAP<sub>1</sub> moieties into a single construct. In enzymatic inhibition assays, both hmFAP<sub>1</sub> and hmFAP<sub>2</sub> demonstrated specific antagonist activity against FAP, with hmFAP<sub>2</sub> exhibiting a 14-fold increase in inhibitory potency compared to hmFAP<sub>1</sub>. Cy5.5 fluorescent derivatives of hmFAP<sub>1</sub> and hmFAP<sub>2</sub> were generated for cell-binding assays in HeLa cells and xenografted tumors with positive FAP expression, revealing enhanced targeting efficacy of Cy5.5-hmFAP<sub>2</sub>. The IC₅₀ values derived from cell-binding curves were 130 nM for hmFAP<sub>1</sub> and 8 nM for hmFAP<sub>2</sub> (<i>P</i> &lt; 0.001). Using DOTA as the chelator, both ligands were radiolabeled with ⁶⁸Ga, yielding stable products [⁶⁸Ga]Ga-DOTA-hmFAP<sub>1</sub> and [⁶⁸Ga]Ga-DOTA-hmFAP<sub>2</sub> for PET imaging. Consistently, [⁶⁸Ga]Ga-DOTA-hmFAP<sub>2</sub> demonstrated superior tumor uptake with high specificity in mice bearing HeLa, MDA-MB-231, and HEK293T xenografts with variable levels of FAP expression. The liver and intestinal radioactivity showed no difference between the groups of mice imaged with [⁶⁸Ga]Ga-DOTA-hmFAP<sub>2</sub> and [⁶⁸Ga]Ga-DOTA-hmFAP<sub>1</sub>.</p> Conclusions <p>hmFAP<sub>2</sub> markedly enhances FAP-targeting efficiency, providing higher binding affinity, improved tumor uptake, and reduced nonspecific distribution compared with its monomeric counterpart. The favorable imaging properties of hmFAP<sub>2</sub> position it as a promising candidate for translation into clinical PET imaging and as a potential scaffold for developing FAP-targeted theranostic agents.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A new 68Ga-labeled dimeric FAP ligand to advance targeted PET imaging of cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月6日

查看全文
  • Feng Li,
  • Chaitanya Kondam,
  • Zhen Yang,
  • Muthuraju Sangu,
  • Jiexiao Chen,
  • Rhonda Holgate,
  • Bingqing Zou,
  • Jiankang Jin,
  • James Nguyen,
  • Philip Martin,
  • Shu Zhang,
  • Yanping Yang,
  • Junhua Mai,
  • Lan Zhou,
  • Diego R. Martin,
  • Zhonglin Liu

摘要

Background

Fibroblast activation protein (FAP) has emerged as a critical biomarker in the tumor microenvironment of various cancers. Radioligands targeting FAP have shown promise for cancer theranostics. To advance cancer imaging, we synthesized a dimeric radioligand based on a 4-quinolinoyl-glycyl-2-cyanopyrrolidine scaffold and conducted studies in cells and mouse tumor models to evaluate its target-binding affinity and PET imaging performance.

Results

OncoFAP, a commercially available FAP ligand, was conjugated via amide coupling with 1,4-butanediamine to generate a monomeric intermediate, hmFAP1. A homodimeric molecule, hmFAP2, was synthesized by tethering two hmFAP1 moieties into a single construct. In enzymatic inhibition assays, both hmFAP1 and hmFAP2 demonstrated specific antagonist activity against FAP, with hmFAP2 exhibiting a 14-fold increase in inhibitory potency compared to hmFAP1. Cy5.5 fluorescent derivatives of hmFAP1 and hmFAP2 were generated for cell-binding assays in HeLa cells and xenografted tumors with positive FAP expression, revealing enhanced targeting efficacy of Cy5.5-hmFAP2. The IC₅₀ values derived from cell-binding curves were 130 nM for hmFAP1 and 8 nM for hmFAP2 (P < 0.001). Using DOTA as the chelator, both ligands were radiolabeled with ⁶⁸Ga, yielding stable products [⁶⁸Ga]Ga-DOTA-hmFAP1 and [⁶⁸Ga]Ga-DOTA-hmFAP2 for PET imaging. Consistently, [⁶⁸Ga]Ga-DOTA-hmFAP2 demonstrated superior tumor uptake with high specificity in mice bearing HeLa, MDA-MB-231, and HEK293T xenografts with variable levels of FAP expression. The liver and intestinal radioactivity showed no difference between the groups of mice imaged with [⁶⁸Ga]Ga-DOTA-hmFAP2 and [⁶⁸Ga]Ga-DOTA-hmFAP1.

Conclusions

hmFAP2 markedly enhances FAP-targeting efficiency, providing higher binding affinity, improved tumor uptake, and reduced nonspecific distribution compared with its monomeric counterpart. The favorable imaging properties of hmFAP2 position it as a promising candidate for translation into clinical PET imaging and as a potential scaffold for developing FAP-targeted theranostic agents.