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Background: Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [18F]FluorThanatrace and [18F]PARPi. Results: [carbonyl-11C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [carbonyl-11C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection. Conclusions: Although [carbonyl-11C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated. [ABSTRACT FROM AUTHOR]

α,β‐aromatic lactams are highly abundant in biologically active molecules, yet so far they cannot be radiolabeled with short‐lived (t1/2=20.3 min), β+‐decaying carbon‐11, which has prevented their application as positron emission tomography tracers. Herein, we developed, optimized, and applied a widely applicable, one‐pot, quick, robust and automatable radiolabeling method for α,β‐aromatic lactams starting from [11C]CO2 using the reagent POCl3⋅AlCl3. This method proceeds via intramolecular Friedel‐Crafts acylation of in situ formed [11C]isocyanates and shows a broad substrate scope for the formation of five‐ and six‐membered rings. We implemented our developed labeling method for the radiosynthesis of the potential PARP1 PET tracer [carbonyl‐11C]DPQ in a clinical radiotracer production facility following the standards of the European Pharmacopoeia. [ABSTRACT FROM AUTHOR]

This article introduces a novel approach to algebraic multigrid methods for large systems of linear equations coming from finite element discretizations of certain elliptic second‐order partial differential equations. Based on a discrete energy made up of edge and vertex contributions, we are able to develop coarsening criteria that guarantee two‐level convergence even for systems of equations such as linear elasticity. This energy also allows us to construct prolongations with prescribed sparsity pattern that still preserve kernel vectors exactly. These allow for a straightforward optimization that simplifies parallelization and reduces communication on coarse levels. Numerical experiments demonstrate efficiency and robustness of the method and scalability of the implementation. [ABSTRACT FROM AUTHOR]