Dataset Information

Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer.

ABSTRACT: Glycolysis, as a multi-step oxidation process, plays important roles in the energy supply for living cells, including malignant tumor cells. Recent studies have revealed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (named PFKFB3), a bifunctional enzyme in glycolysis, is upregulated in a variety of malignant solid tumors and has been regarded as a potential biomarker for the diagnosis and treatment of tumor patients. Based on the structure of selective PFKFB3 inhibitors, we designed and synthesized a radio-metal radiolabeled small molecule, ⁶⁸Ga-5, which also showed potent selectivity in enzymatic and biochemical tests (with an IC₅₀ value of 12.5 nM). According to further in vitro and in vivo evaluations, ⁶⁸Ga-5 showed promising properties as a PET ligand, and selective accumulation in PFKFB3-positive tumors was observed in PET images (with max SUV values of 0.60). Our results indicated that radio-metal radiolabeled aminoquinoxaline derivative, as represented by ⁶⁸Ga-5, held the potential to be developed as selective PFKFB3-targeted PET tracers, and further investigation and optimization would also be required for this scaffold.

SUBMITTER: Chen F

PROVIDER: S-EPMC10073729 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer.

Chen Feng F Wu Yi Y Ma Yixuan Y Yin Honghai H Su Feijing F Huang Rui R Wu Xiaoai X Liu Qian Q

Frontiers in chemistry 20230322

Glycolysis, as a multi-step oxidation process, plays important roles in the energy supply for living cells, including malignant tumor cells. Recent studies have revealed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (named PFKFB3), a bifunctional enzyme in glycolysis, is upregulated in a variety of malignant solid tumors and has been regarded as a potential biomarker for the diagnosis and treatment of tumor patients. Based on the structure of selective PFKFB3 inhibitors, we designed ...[more]

PMID: 37035116

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Project description:We developed a first-of-kind dasatinib-derivative imaging agent, 18F-SKI-249380 (18F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using 18F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of 18F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of 18F-SKI. In total, 27 tumor lesions were analyzed, with a median SUVpeak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau (n = 2). Like dasatinib, 18F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion:18F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.

Project description:BackgroundCancer patients undergoing Doxorubicin (DOX) treatment are susceptible to acute and chronic cardiac anomalies, including aberrant arrhythmias, ventricular dysfunction, and heart failure. To stratify patients at high risk for DOX -related heart failure (CHF), diagnostic techniques have been sought. While echocardiography is used for monitoring LVEF and LV volumes due to its wide-availability and cost-efficiency, it may not identify early stages of the initiation of DOX-induced systolic heart failure. To address these limitations, PET tracers could also provide noninvasive assessment of early and reversible metabolic changes of the myocardium.ObjectiveHerein, we report a preliminary investigation of 68Ga-Galmydar potential to monitor Dox-induced cardiomyopathy in vivo, ex vivo, and in cellulo employing both nuclear- and optical imaging.Methods and resultsTo assess 68Ga-Galmydar ability for monitoring DOX-induced cardiomyopathy, microPET imaging was performed 5 d post treatment of rats either with a single dose of DOX (15 mg/kg) or vehicle as a control (saline) and images were co-registered for anatomical reference using CT. Following tail-vein injection of the radiotracer in rats at 60 min, micro-PET/CT static scan (10 min acquisition), 68Ga-Galmydar demonstrated 1.91-fold lower uptake in hearts of DOX-treated (standard uptake value; SUV: 0.92, n = 3) rats compared with their vehicle treated (SUV: 1.76, n = 3) control counterparts. For correlation of PET imaging data, post-imaging quantitative biodistribution studies were also performed, wherein excised organs were counted for γ activity, and normalized to injected dose. The post imaging pharmacokinetic data also demonstrated heart uptake values of 2.0 fold lower for DOX treated rats(%ID/g; DOX: 0.44 ± 0.1, n = 3) compared to their vehicle-treated controls (%ID/g; Control: 0.89 ± 0.03, n = 3, p = 0.04). Employing the fluorescent traits of Galmydar, live cell fluorescence imaging indicated a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment, while indicating dose-dependent and time-dependent uptake profiles. Following depolarization of electronegative transmembrane gradients at the mitochondrial membrane, the uptake of the probe was decreased in H9c2 cells, and the uptake profiles were found to be identical, using both fluorescence and radiotracer bioassays. Finally, the decreased uptake of the metalloprobe in H9c2 cells also correlated with caspase-3 expression resulting from DOX-induced cardiotoxicity and cell death.Conclusions68Ga-Galmydar could provide a noninvasive assessment of DOX-related and likely reversible metabolic changes at earliest stages. Further studies with other chemotherapeutics (potentially capable of inducing cardiomyopathy) are underway.

Dataset Information

Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer.

Publications

Synthesis, radiolabeling, and evaluation of 68Ga-labeled aminoquinoxaline derivative as a potent PFKFB3-targeted PET tracer.

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