Synthesis, Screening, and Evaluation of Theranostic Molecular CPCR4-Based Probe Targeting CXCR4
Tingting Yang1,2, Dai Shi1,2, Qingyu Lin1,2
1Shanghai Institute of Medical Imaging, Shanghai 200032, China.
Abstract:
Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.
Insights
This study developed novel theranostic tracers targeting chemokine receptor 4 (CXCR4) for improved cancer diagnosis and therapy. Compound 6, labeled with iodine-124 for imaging and iodine-131 for therapy, demonstrated superior tumor targeting and therapeutic efficacy with minimal side effects.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Chemokines and their receptors, particularly chemokine (C-X-C motif) receptor 4 (CXCR4), are crucial in cancer development and progression.
- CXCR4 is frequently overexpressed in various malignancies, making it a promising target for integrated diagnosis and therapy.
- Existing theranostic agents like [68Ga]Ga-pentixafor show potential, but their therapeutic counterparts require optimization to reduce off-target effects, such as hepatic biodistribution.
Purpose of the Study:
- To synthesize and evaluate novel theranostic molecular tracers with enhanced CXCR4 targeting capabilities for improved cancer management.
- To compare the efficacy of newly developed tracers against established agents in preclinical models.
- To identify a lead compound for both diagnostic imaging and therapeutic application in CXCR4-expressing tumors.
Main Methods:
- Synthesis of six novel tracers based on the pentixafor pharmacophore, including [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4), and [124I]I-6 ([124I]I-pentixafor-Ga).
- Evaluation of tracers using CXCR4-expressing (Daudi) and low-CXCR4-expressing (MM.1S) cell lines.
- In vivo evaluation using PET/SPECT imaging to assess target-nontarget ratios and biodistribution.
- Therapeutic efficacy assessment in tumor-bearing animal models treated with the optimized therapeutic agent ([131I]I-6).
Main Results:
- All synthesized tracers demonstrated high radiochemical purity (>95%).
- [124I]I-6 exhibited the most favorable target-nontarget ratio in PET/SPECT imaging compared to other tracers and [68Ga]Ga-pentixafor.
- [124I]I-6 showed lower uptake in non-target organs and superior targeting of CXCR4.
- Therapeutic administration of [131I]I-6 significantly reduced tumor volume in animal models without notable side effects.
Conclusions:
- Compound 6, developed as [124I]I-6 for diagnosis and [131I]I-6 for therapy, demonstrates excellent CXCR4-targeting affinity and theranostic potential.
- The developed tracers offer improved performance over existing agents, particularly in terms of target-nontarget ratios and reduced off-target accumulation.
- [124I]I-6 and [131I]I-6 represent promising candidates for the integrated diagnosis and treatment of tumors with high CXCR4 expression.
