RESUMO
BACKGROUND: In the last decade the development of new PSMA-ligand based radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research. The most promising derivative in terms of interaction with the antigen and clinical properties has been found to be "PSMA-617", and its lutetium-177 radiolabelled version has recently been approved by EU and USA regulatory agencies for therapeutic purposes. For the above reasons, the development of new derivatives of PSMA-617 radiolabelled with fluorine-18 may still be of great interest. This paper proposes the comparison of two different PSMA-617 derivatives functionalized with NODA and RESCA chelators, respectively, radiolabelled via [18F]AlF2+ complexation. RESULTS: The organic synthesis of two PSMA-617 derivatives and their radiolabelling via [18F]AlF2+ complexation resulted to proceed efficiently and successfully. Moreover, stability in solution and in plasma has been evaluated. The whole radiosynthesis procedure has been fully automated, and the final products have been obtained with radiochemical yield and purity potentially suitable for clinical studies. The biodistribution of the two derivatives was performed both in prostate cancer and glioma tumour models. Compared with the reference [18F]F-PSMA-1007 and [18F]F-PSMA-617-RESCA, [18F]F-PSMA-617-NODA derivative showed a higher uptake in both tumors, faster clearance in non-target organs, and lower uptake in salivary glands. CONCLUSION: PSMA-617 NODA and RESCA derivatives were radiolabelled successfully via [18F]AlF2+ chelation, the former being more stable in solution and human plasma. Moreover, preclinical biodistribution studies showed that [18F]F-PSMA-617-NODA might be of potential interest for clinical applications.
RESUMO
The tyrosine kinase, colony-stimulating factor 1 receptor (CSF1R), has attracted attention as a potential biomarker of neuroinflammation for imaging studies with positron emission tomography (PET), especially because of its location on microglia and its role in microglia proliferation. The development of an effective radiotracer for specifically imaging and quantifying brain CSF1R is highly challenging. Here we review the progress that has been made on PET tracer development and discuss issues that have arisen and which remain to be addressed and resolved.
RESUMO
[11C]CPPC has been advocated as a radioligand for colony-stimulating factor 1 receptor (CSF1R) with the potential for imaging neuroinflammation in human subjects with positron emission tomography (PET). This study sought to prepare fluoro analogs of CPPC with higher affinity to provide the potential for labeling with longer-lived fluorine-18 (t 1/2 = 109.8 min) and for delivery of higher CSF1R-specific PET signal in vivo. Seven fluorine-containing analogs of CPPC were prepared and four were found to have high inhibitory potency (IC50 in low to sub-nM range) and selectivity at CSF1R comparable with CPPC itself. One of these, a 4-fluoromethyl analog (Psa374), was investigated more deeply by labeling with carbon-11 (t 1/2 = 20.4 min) for PET studies in mouse and monkey. [11C]Psa374 showed high peak uptake in monkey brain but not in mouse brain. Pharmacological challenges revealed no CSF1R-specific binding in either species at baseline. [11C]CPPC also failed to show specific binding at baseline. Moreover, both [11C]Psa374 and [11C]CPPC showed brain efflux transporter substrate behavior in both species in vivo, although Psa374 did not show liability toward human efflux transporters in vitro. Further development of [11C]Psa374 in non-human primate models of neuroinflammation with demonstration of CSF1R-specific binding would be required to warrant the fluorine-18 labeling of Psa374 with a view to possible application in human subjects.
RESUMO
Pd(0)-mediated 11C-carbonylation of aryl(mesityl)iodonium salts followed by suitable quench provides a rapid room-temperature two-pot procedure for labeling arylcarboxylic acids and amide derivatives with the short-lived positron emitter carbon-11 (t1/2 = 20.4 min) in generally good to high yields (up to 71%). High product ring selectivity (≥13) was achieved when using mesityl as a spectator group in the diaryliodonium salt precursors. This process has potential for preparing new radiotracers for molecular imaging with positron emission tomography.