Avidin/Biotin Bioinspired Platform for Dual In Vivo 18 F-PET/NIRF Molecular Imaging

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Monitoring therapeutic efficacy of sunitinib using [(18)F]FDG and [(18)F]FMISO PET in an immunocompetent model of luminal B (HER2-positive)-type mammary carcinoma

Clinical studies implying the sunitinib multi-kinase inhibitor have led to disappointing results for breast cancer care but mostly focused on HER2-negative subtypes. Preclinical researches involving this drug mostly concern Triple Negative Breast Cancer (TNBC) murine models. Here, we explored the therapeutic efficacy of sunitinib on a PyMT-derived transplanted model classified as luminal B (HER2-positive) and monitored the response to treatment using both in vivo and ex vivo approaches.[br/]Tumour-induced animals were treated for 9 (n = 7) or 14 (n = 8) days with sunitinib at 40 mg/kg or with vehicle only. Response to therapy was assessed in vivo by monitoring glucose tumour metabolism and hypoxia using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and [(18)F]fluoromisonidazole ([(18)F]FMISO) Positron Emission Tomography (PET). After primary tumour excision, ex vivo digital microscopy was performed on treated and control samples to estimate vascular density (CD31), apoptosis (Tunel), proliferation (Ki-67), Tumour-Associated Macrophage (TAM) infiltration (F4/80), metabolism (GLUT1) and cellular response to hypoxia (HIF1 alpha). The drug impact on the metastasis rate was evaluated by monitoring the PyMT gene expression in the lungs of the treated and control groups.[br/]Concomitant with sunitinib-induced tumour size regression, [(18)F]FDG PET imaging showed a stable glycolysis-related metabolism inside tumours undergoing treatment compared to an increased metabolism in untreated tumours, resulting at treatment end in 1.5 less [(18)F]FDG uptake in treated (n = 4) vs control (n = 3) tumours (p < 0.05). With this small sample, [(18)F]FMISO PET showed a non-significant decrease of hypoxia in treated vs control tumours. The drug triggered a 4.9 fold vascular volume regression (p < 0.05), as well as a 17.7 fold induction of tumour cell apoptosis (p < 0.001). The hypoxia induced factor 1 alpha (HIF1 alpha) expression was twice lower in the treated group than in the control group (p < 0.05). Moreover, the occurrence of lung metastases was not reduced by the drug.[br/][(18)F]FDG and [(18)F]FMISO PET were relevant approaches to study the response to sunitinib in this luminal B (HER2-positive) model. The sunitinib-induced vascular network shrinkage did not significantly increase tumour hypoxia, suggesting that tumour regression was mainly due to the pro-apoptotic properties of the drug. Sunitinib did not inhibit the metastatic process in this PyMT transplanted model

In vivo validation in rat and monkey of RAC-9-{(1-[18F]flouro-3-hydroxy-2-propoxy)methyl}guanine: A radiopharmaceutical for gene therapy

SCOPUS: cp.jFLWNOinfo:eu-repo/semantics/publishe

Experimental Approach to Evaluate the 11C Perfusion and Diffusion in Small Animal Tissues for HadronPET Applications

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Automated two-step manufacturing of [11C]glyburide radiopharmaceutical for PET imaging in humans

International audienceIntroduction: Glyburide is an approved anti-diabetes drug binding to the sulfonylurea receptors-1 (SUR-1) and substrate of solute carrier (SLC) transporters, which can be isotopically radiolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [11C]glyburide and a full European Pharmacopeia 9.7 compliant quality control to use [11C]glyburide in PET imaging clinical trials.Methods: Different conditions were explored to afford non-radioactive glyburide by one or two-step methylation. These experiments were monitored by UPLC-MS. The optimized process was applied to the automated radiosynthesis of [11C]glyburide using a TRACERlab® FX C Pro. A complete quality control according to Pharmacopeia guidelines was realized.Results: One-step methylation revealed regioselectivity issues as methylation occurred preferentially on the sulfonylurea moiety. Two-step approach by methylation followed by reaction with cyclohexyl isocyanate afforded glyburide without formation of methylated side products. Ready-to-inject [11C]glyburide was obtained in 5% non-decay corrected radiochemical yield and 110 ± 20 GBq/μmol molar activity within 40 min (n = 8). [11C]Glyburide quality control was compliant with the Pharmacopeia requirements.Conclusions: We have described a highly reproducible and automated two-step radiosynthesis of [11C]glyburide which was qualified as a radiopharmaceutical for human injection. This whole manufacturing process is currently being used to conduct a clinical trial to elucidate the hepatic transport of drugs.Advances in knowledge: Compared to previously reported radiosynthesis of [11C]glyburide, this work provides an original and reproducible approach which can be transferred to any PET centre interested in using this radiotracer for preclinical or clinical imaging.Implication for patient care: This work provides a method to manufacture [11C]glyburide for human PET imaging. This radiopharmaceutical could be used to elucidate the role of transporters in drug exposure of different organs or to monitor brain recovery after central nervous system (CNS) injuries

Imaging the impact of cyclosporin A and dipyridamole on P-glycoprotein (ABCB1) function at the blood-brain barrier: A [11C]-N-desmethyl-loperamide PET study in nonhuman primates

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An original radio-biomimetic approach to synthesize radiometabolites for PET imaging

International audienceTo fully exploit the potential of positron emission tomography (PET) imaging to assess drug distribution and pharmacokinetics in the central nervous system, the contribution of radiometabolites to the PET signal has to be determined for correct interpretation of data. However, radiosynthesis and extensive study of radiometabolites are rarely investigated and very challenging for complex drugs. Therefore, an original radio-biomimetic (RBM) approach was developed to rapidly synthesize radiometabolites and non-invasively investigate their kinetics with PET imaging. This method enabled the challenging radiosynthesis of [11C]nor-buprenorphine ([11C]nor-BUP), the main metabolite of buprenorphine (BUP) which has been identified as a substrate of the P-glycoprotein (P-gp) transport function at the blood-brain barrier (BBB). Biomimetic conditions using cytochromes P450 3A4 to convert BUP into nor-BUP were optimized taking into account the short half-life of carbon-11 (t1/2 = 20.4 min). Those conditions afforded 32% of conversion within 20 min and were applied to the biomimetic radiosynthesis of [11C]nor-BUP from [11C]BUP. Automated radiosynthesis of [11C]BUP according to a procedure described in the literature followed by optimized RBM conditions afforded [11C]nor-BUP in 1.5% decay-corrected radiochemical yield within 90 min and 90 ± 15 GBq/μmol molar activity. HPLC quality control showed chemical and radiochemical purities above 98%. To demonstrate the applicability of the RBM approach to preclinical studies, brain PET images in rats showed a drastic lower uptake of [11C]nor-BUP (0.067 ± 0.023%ID/cm-3) compared to [11C]BUP (0.436 ± 0.054%ID/cm-3). P-gp inhibition using Tariquidar increased the brain uptake of [11C]nor-BUP (0.557 ± 0.077%ID/cm-3)