Design, development and bio-evaluation of a novel radio-ligand 99mTc-THQ-DTPA as a sigma 2 receptor specific breast tumor imaging agent
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Investigations on the GaIII Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue
Published on: August 17, 2016
Vishakha Chaudhary1, Shubhra Chaturvedi2, Anju Wadhwa3
1Kirori Mal College, University of Delhi, North Campus, University Enclave, Delhi 110007, India; Department of Radiological Nuclear and Imaging Science, INMAS, DRDO, Timarpur, Delhi 110054, India.
Abstract:
Over-expression of sigma-2 receptor in cancer cells provides an opportunity to develop molecular probes for diagnosis, even for non-receptor specific malignancies like triple negative breast cancers. In this work, a novel sigma-2 receptor ligand [THQ-DTPA] has been synthesized and characterized using 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (THQ) and diethylenetriaminepentaacetic acid (DTPA). The ligand is further chelated with 99mTc for application as metal based radiotracer [99mTc-THQ-DTPA]. Radiolabelling with 99mTc was achieved in an excellent yield of 98.0 ± 0.5% using stannous chloride as a reducing agent. The radioligand was found to be stable in human serum up-to 24 h, bio-compatible with less than 4% hemolysis, and exhibited high binding with sigma receptors isolated from rat liver membrane (Kd of 16.32 ± 4.93 nM and Bmax of 0.5232 ± 0.06 pmol/mg). Bio-distribution studies in triple-negative breast tumor bearing nude mice showed high tumor uptake after 30 min of injection with tumor/muscle (T/M) ratio of 3.58 ± 0.09. At 240 min, the T/M ratio (2.84 ± 0.20) decreased by 35% when administered in sigma blocked tumor bearing mice (1.81 ± 0.16) suggesting the selectivity of the ligand. Tumor imaging in gamma camera indicated a contrast of 3.56 at 30 min p.i. The above findings indicate that the ligand 99mTc-THQ-DTPA binds to sigma-2 receptors with high affinity and has potential for triple-negative breast tumor imaging.
Insights
A new radiotracer, 99mTc-THQ-DTPA, shows high affinity for sigma-2 receptors. This molecular probe demonstrates potential for imaging triple-negative breast tumors, offering a new diagnostic avenue.
Area of Science:
- Radiochemistry
- Molecular Imaging
- Oncology
Background:
- Over-expression of sigma-2 receptors in various cancers, including triple-negative breast cancer, presents a target for molecular probes.
- Developing specific ligands for sigma-2 receptors is crucial for targeted cancer diagnosis and therapy.
Purpose of the Study:
- To synthesize and characterize a novel sigma-2 receptor ligand, THQ-DTPA, and its technetium-99m (99mTc) radiolabeled form, 99mTc-THQ-DTPA.
- To evaluate the potential of 99mTc-THQ-DTPA as a radiotracer for imaging triple-negative breast tumors.
Main Methods:
- Synthesis and characterization of the THQ-DTPA ligand.
- Radiolabeling of the ligand with 99mTc using stannous chloride.
- In vitro stability and biocompatibility assays (hemolysis).
- In vitro binding studies with sigma receptors.
- In vivo biodistribution and tumor uptake studies in tumor-bearing mice.
- Gamma camera imaging.
Main Results:
- High radiolabeling yield (98.0 ± 0.5%) and excellent stability of 99mTc-THQ-DTPA in human serum for 24 hours.
- Demonstrated high binding affinity (Kd of 16.32 ± 4.93 nM) to sigma receptors.
- Significant tumor uptake in triple-negative breast tumor models with high tumor-to-muscle ratios (3.58 ± 0.09 at 30 min).
- Selective tumor targeting confirmed by blocking studies and gamma camera imaging.
Conclusions:
- The novel radiotracer 99mTc-THQ-DTPA exhibits high affinity and selectivity for sigma-2 receptors.
- This radiotracer shows significant potential for effective in vivo imaging of triple-negative breast tumors.
