Development and Preclinical Evaluation of a Gallium-68 Labeled Novel Diagnostic Tracer for Visualizing ALK Expression in Tumor.

in European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences by Zhen-Peng Yu, Ke-Xin Sun, Dan Zhang, Zhi-Qiang Yu, Deng-Yun Chen, Hong Zhu, Hongwei Si, Peng-Fei Dai

TLDR

  • A novel PET/MR imaging tracer, Ga-DOTA-CTB, was developed based on ceritinib scaffold to monitor ALK expression levels during targeted therapy in ALK-positive tumors.

Abstract

Anaplastic lymphoma kinase (ALK) is prominently expressed in numerous malignant tumors, which lead to aberrant tumor proliferation, invasion and metastasis. Ceritinib (LDK378), as second-generation targeted drugs, has been used to treat advanced ALK-positive non-small cell lung cancer (NSCLC). Herein, we sought to develop a novel ALK-positron emission tomography/magnetic resonance (PET/MR) tracerGa-DOTA-CTB (Ga labeled ceritinib) based on ceritinib scaffold to monitor the ALK expression levels during targeted therapy with ceritinib. TheGa-DOTA-CTB radiotracer, obtained via a simple labeling procedure, exhibits favorable radiochemical purity, stability, and pharmacokinetic properties. Subsequently, cellular uptake experiments have demonstrated thatGa-DOTA-CTB could be accumulated in H2228 cells. Imaging and biodistribution experiments have revealed significant uptake of the radiotracer in the tumors of the experimental group, while tumors in the blocking group, which were saturated with an excess of precursor, exhibited a markedly reduced level of radioactivity. These empirical findings suggest thatGa-DOTA-CTB holds substantial potential as a novel PET/MR imaging tracer for ALK-positive tumors.

Overview

  • The study aims to develop a novel ALK-positron emission tomography/magnetic resonance (PET/MR) tracer, Ga-DOTA-CTB, based on ceritinib scaffold to monitor ALK expression levels during targeted therapy with ceritinib.
  • The study uses ceritinib, a second-generation targeted drug, to treat advanced ALK-positive non-small cell lung cancer (NSCLC).
  • The primary objective of the study is to develop a PET/MR imaging tracer to monitor ALK expression levels in ALK-positive tumors.

Comparative Analysis & Findings

  • Ga-DOTA-CTB exhibits favorable radiochemical purity, stability, and pharmacokinetic properties, making it a promising PET/MR imaging tracer.
  • In cellular uptake experiments, Ga-DOTA-CTB is accumulated in H2228 cells, indicating its ability to target ALK-positive tumors.
  • Imaging and biodistribution experiments show significant uptake of the radiotracer in tumors, while blocking with an excess of precursor reduces the level of radioactivity, indicating specific binding to ALK-positive tumors.

Implications and Future Directions

  • Ga-DOTA-CTB holds potential as a novel PET/MR imaging tracer for ALK-positive tumors, enabling non-invasive monitoring of ALK expression levels during targeted therapy.
  • Future studies can explore the potential of Ga-DOTA-CTB in other types of ALK-positive cancers, such as lymphoma.
  • The development of Ga-DOTA-CTB as a PET/MR imaging tracer may lead to improved patient management and treatment outcomes for ALK-positive tumors.
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