Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [F-18]olaparib in mouse models of glioma

Purpose Radiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [F-18]olaparib and the injected mass of [F-Total]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models. Methods [F-18]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [F-Total]olaparib (varying injected mass: 0.04-8.0 mu g, and molar activity: 1-320 GBq/mu mol). Results Selective uptake of [F-18]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [F-Total]olaparib (mu g) but not the molar activity. An injected mass of 1 mu g resulted in the highest tumour uptake (up to 6.9 +/- 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [F-Total]olaparib resulted in lower relative tumour uptake (%ID/g; P 0.5 mu g). Conclusion Our findings show that the injected mass of [F-Total]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy

PET Imaging of Copper Trafficking in a Mouse Model of Alzheimer Disease

Alzheimer disease (AD) is a fatal neurodegenerative disorder characterized by progressive neuronal loss and cognitive decline. The lack of reliable and objective diagnostic markers for AD hampers early disease detection and treatment. Growing evidence supports the existence of a dysregulation in brain copper trafficking in AD. The aim of this study was to investigate brain copper trafficking in a transgenic mouse model of AD by PET imaging with 64Cu, to determine its potential as a diagnostic biomarker of the disorder. Methods: Brain copper trafficking was evaluated in 6- to 8-mo-old TASTPM transgenic mice and age-matched wild-type controls using the 64Cu bis(thiosemicarbazone) complex 64Cu-GTSM (glyoxalbis(N4-methyl-3-thiosemicarbazonato) copper(II)), which crosses the blood–brain barrier and releases 64Cu bioreductively into cells. Animals were intravenously injected with 64Cu-GTSM and imaged at 0–30 min and 24–25 h after injection. The images were analyzed by atlas-based quantification and texture analysis. Regional distribution of 64Cu in the brain 24 h after injection was also evaluated via ex vivo autoradiography and compared with amyloid-β plaque deposition in TASTPM mice. Results: Compared with controls, in TASTPM mice PET image analysis demonstrated significantly increased (by a factor of ∼1.3) brain concentration of 64Cu at 30 min (P < 0.01) and 24 h (P < 0.05) after injection of the tracer and faster (by a factor of ∼5) 64Cu clearance from the brain (P < 0.01). Atlas-based quantification and texture analysis revealed significant differences in regional brain uptake of 64Cu and PET image heterogeneity between the 2 groups of mice. Ex vivo autoradiography showed that regional brain distribution of 64Cu at 24 h after injection did not correlate with amyloid-β plaque distribution in TASTPM mice. Conclusion: The trafficking of 64Cu in the brain after administration of 64Cu-GTSM is significantly altered by AD-like pathology in the TASTPM mouse model, suggesting that 64Cu-GTSM PET imaging warrants clinical evaluation as a diagnostic tool for AD and possibly other neurodegenerative disorders