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Development of 99mTc-Labeled Complexes with a Niraparib HYNIC Derivative for PARP-Positive Tumor Imaging
Qianna Wang1, Junhong Feng1,2, Yuhao Jiang1,3
1Key Laboratory of Radiopharmaceuticals of the Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), College of Chemistry, Beijing Normal University, Beijing 100875, P. R. China.
Abstract:
As an enzyme that plays an important role in DNA repair, poly(ADP-ribose) polymerase-1 (PARP-1) has become a popular target for cancer therapy. Nuclear medicine molecular imaging technology, supplemented by radiolabeled PARP-1 inhibitors, can accurately determine the expression level of PARP-1 at lesion sites to help patients choose an appropriate treatment plan. In this work, niraparib was modified with a hydrazinonicotinamide (HYNIC) group to generate the ligand NPBHYNIC, which has an in vitro affinity (IC50) of 450.90 nM for PARP-1. The ligand NPBHYNIC was labeled with technetium-99m and six different coligands to yield [99mTc]Tc-(X/tricine)-NPBHYNIC (X = TPPTS, TPPMS, PSA, PDA, NIC and ISONIC). These complexes were hydrophilic and exhibited good stability in vitro, and low levels of these complexes were taken up by nontarget organs and tissues in Kunming mice. Among these complexes, [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC and [99mTc]Tc-(NIC/tricine)-NPBHYNIC were selected for biodistribution in HeLa tumor-bearing BALB/c nude mice at 2 h post injection. The results revealed that the tumor uptake of [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC (1.02 ± 0.07% ID/g) was greater than that of [99mTc]Tc-(NIC/tricine)-NPBHYNIC (0.36 ± 0.05% ID/g). Additionally, in biodistribution, single-photon emission computed tomography/computed tomography (SPECT/CT) and radioautography experiments, the tumor uptake of [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC was significantly reduced in the blocked group, indicating PARP-1 specificity. Therefore, it has potential for use as a niraparib-based tumor imaging agent that targets PARP-1.
Insights
Researchers developed a new technetium-99m-labeled imaging agent targeting poly(ADP-ribose) polymerase-1 (PARP-1) for cancer therapy. The agent, [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC, showed promising tumor uptake and specificity in preclinical studies.
Area of Science:
- Nuclear Medicine
- Radiochemistry
- Oncology
Background:
- Poly(ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in DNA repair and a therapeutic target in cancer.
- Nuclear medicine imaging with radiolabeled inhibitors can assess PARP-1 expression for treatment selection.
Purpose of the Study:
- To develop and evaluate a novel technetium-99m ([99mTc])-labeled imaging agent based on niraparib for targeting PARP-1 in tumors.
Main Methods:
- Niraparib was modified to create the HYNIC-conjugated ligand NPBHYNIC.
- NPBHYNIC was radiolabeled with [99mTc]Tc and various coligands.
- Complex stability, biodistribution, and tumor targeting specificity were assessed in vitro and in vivo using mouse models.
Main Results:
- The [99mTc]Tc-labeled complexes were hydrophilic and stable in vitro.
- [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC demonstrated higher tumor uptake (1.02 ± 0.07% ID/g) compared to [99mTc]Tc-(NIC/tricine)-NPBHYNIC (0.36 ± 0.05% ID/g).
- Biodistribution and SPECT/CT imaging confirmed the PARP-1 specificity of [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC.
Conclusions:
- [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC is a promising PARP-1-specific tumor imaging agent.
- This agent has potential for guiding cancer therapy selection based on PARP-1 expression levels.
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