Romain Bejot

Convergent 18F radiosynthesis: A new dimension for radiolabelling

The availability of radiolabelled probes is important for in vivo studies by positron emission tomography (PET). Among the frontier challenges in 18F-radiochemistry are the interconnected goals of increasing synthetic efficiency and diversity in the construction of 18F-labelled radiotracers. 18F-Radioretrosynthetic strategies implemented to date are typically linear sequences of transformations designed with the aim of introducing the 18F-label ideally in the last step or at least as late as possible. Here we report that convergent 18F-radiochemistry allows for the rapid assembly of functionalised 18F-radiotracers from readily accessible 18F-labelled prosthetic groups. Using multicomponent reactions for proof of concept, Ugi-4CR, Passerini-3CR, Biginelli-3CR and Groebke-3CR were performed successfully using 18F-benzaldehydes and these highly convergent reactions delivered, in high radiochemical yield (RCY), structurally complex 18F-radiotracers with the label positioned on an aryl motif not responsive to direct nucleophilic fluorination. These data establish an unprecedented connection between radiochemistry for PET and the field of multicomponent chemistry and demonstrate that convergent retroradiosynthesis is a powerful strategy expanding dramatically the scope of 18F-prosthetic group radiochemistry. The preparation of 18F-labelled prosthetic groups from [18F]fluoride ion is commonly performed in many labelling laboratories, so the concept of convergent 18F-radiosynthesis can easily be applied immediately.

Pre-clinical evaluation of a 3-nitro-1,2,4-triazole analogue of [18F]FMISO as hypoxia-selective tracer for PET.

Hypoxia in solid tumours is associated with the promotion of various metabolic mechanisms and induces resistance to radio- and chemotherapy. Non-invasive positron emission tomography (PET) or single photon emission computed tomography by use of selective biomarkers has emerged as valuable tools for the detection of hypoxic areas within tumours so treatment can be modified accordingly. The aim of this investigation was to evaluate [(18)F]3-NTR, a 3-nitro-1,2,4-triazole analogue (N(1) substituted) of [(18)F]FMISO as a potential hypoxia selective tracer. 3-NTR and its (18)F-radiolabelled isotopic isomer were synthesised and compared with FMISO in vitro and in vivo. Their physicochemical properties were measured, the enzymatic reduction was evaluated, and the reactivity of their metabolites was investigated. Biodistribution and PET scans were performed on CBA mice bearing hypoxic CaNT tumour cells, using (18)F-labelled versions of the tracers. [(18)F]3-NTR uptake within hypoxic cells was lower than [(18)F]FMISO and [(18)F]3-NTR did not exhibit any better selectivity than FMISO as a PET tracer in vivo. Both (18)F-radiolabelled compounds are relatively evenly distributed within the whole body and the radioactive uptake within hypoxic tumours reaches a maximum at 30 min post injection and decreases thereafter. Xanthine oxidase exhibited a nitroreductase activity toward 3-NTR under anaerobic conditions, but reduced metabolites did not bind covalently. It is confirmed that 3-NTR is an electron acceptor. It is postulated that radiolabelled metabolites and fragments of [(18)F]3-NTR are freely diffusing due to their poor binding capacities. Thus [(18)F]3-NTR cannot be used as a hypoxia selective tracer for PET. The investigation provides insights into the importance of the propensity to form covalent adducts for such biomarkers.

A fluorous and click approach for screening potential PET probes: Evaluation of potential hypoxia biomarkers

Radiopharmaceuticals for nuclear imaging are essentially targeting molecules, labeled with short-lived radionuclides (e.g., F-18 for PET). A significant drawback of radiopharmaceuticals development is the difficulty to access radiolabeled molecule libraries for initial in vitro evaluation, as radiolabeling has to be optimized for each individual molecule. The present paper discloses a method for preparing libraries of (18)F-labeled radiopharmaceuticals using both the fluorous-based (18)F-radiochemistry and the Huisgen 1,3-dipolar (click) conjugation reaction. As a proof of concept, this approach allowed us to obtain a series of readily accessible (18)F-radiolabeled nitroaromatic molecules, for exploring their structure-activity relationship and further in vitro evaluation of their hypoxic selectivity.

Orthogonal 18F and 64Cu labelling of functionalised bis(thiosemicarbazonato) complexes

The synthesis of three pairs of orthogonally labelled fluorinated Cu bis(thiosemicarbazonato) complexes is presented. These are the first examples of (18)F-labelled Cu(II)-complexes designed to serve as new hypoxia selective PET tracers and as mechanistic probes to study the mode of action of this class of markers. In vitro evaluation revealed that the fluorinated Cu-complex derived from amide coupling is suitable for in vivo work.

Molecular Targeting of Breast Cancer: Molecular Imaging and Therapy

Breast cancer is increasing at an alarming rate in women around the world, where medical biology is confronted by this disease on two crucial fronts. The first step is the early accurate diagnosis, which is very critical and the second step involves the appropriate clinical management. The current trend in molecular imaging of breast cancer provides not only an excellent tool in diagnosing the disease but also useful in validating the potentiality targeted of a pharmaceutical interventions. This review addresses the effectiveness of imaging technologies to resolve the molecular characterization and pathological evidences in breast cancer. The focus is on the present practices in breast cancer imaging, specifically targeting cellular machineries such as hormone receptors and angiogenic factors.