Proof of concept of a new plasma complement Factor H from waste plasma fraction.

Introduction: Complement factor H (FH) is a major regulator of the complement alternative pathway, its mutations predispose to an uncontrolled activation in the kidney and on blood cells and to secondary C3 deficiency. Plasma exchange has been used to correct for FH deficiency and although the therapeutic potential of purified FH has been suggested by experiments in animal models, a clinical approved FH concentrate is not yet available. We aimed to develop a purification process of FH from a waste fraction rather than whole plasma allowing a more efficient and ethical use of blood and plasma donations.

Raclopride-Molecularly Imprinted Polymers: A Promising Technology for Selective [C]Raclopride Purification.

In this work, we developed a novel approach to purify [C]Raclopride ([C]RAC), an important positron emission tomography radiotracer, based on tailored shape-recognition polymers, with the aim to substitute single-pass HPLC purification with an in-flow trap & release process. Molecular imprinting technology (MIT) applied to solid phase extraction (MISPE) was investigated to develop a setting able to selectively extract [C]RAC in a mixture containing a high amount of its precursor, (S)-O-Des-Methyl-Raclopride (DM-RAC). Two imprinted polymers selective for unlabeled RAC and DM-RAC were synthesized through a radical polymerization at 65 °C using methacrylic acid and trimethylolpropane trimethacrylate in the presence of template molecule (RAC or DM-RAC).

Novel Strategy for Non-Aqueous Bioconjugation of Substituted Phenyl-1,2,4-triazole-3,5-dione Analogues.

A novel 4-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]-1,2,4-triazole-3,5-dione () was synthesised as a potential [F]radio-prosthetic group for radiolabelling peptides and proteins via selective bioconjugation with the phenolic side chains of tyrosine residues. Preliminary conjugation tests revealed the rapid hydrolysis of under semi-aqueous conditions; these results led to further investigation into the electronic substituent effects of PTAD derivatives and corresponding hydrolytic stabilities. Five derivatives of with substituents of varying electron donating and withdrawing effects were synthesised for the investigation.

Kinetic isotope effects and synthetic strategies for deuterated carbon-11 and fluorine-18 labelled PET radiopharmaceuticals.

The deuterium labelling of pharmaceuticals is a useful strategy for altering pharmacokinetic properties, particularly for improving metabolic resistance. The pharmacological effects of such metabolites are often assumed to be negligible during standard drug discovery and are factored in later at the clinical phases of development, where the risks and benefits of the treatment and side-effects can be wholly assessed. This paradigm does not translate to the discovery of radiopharmaceuticals, however, as the confounding effects of radiometabolites can inevitably show in preliminary positron emission tomography (PET) scans and thus complicate interpretation.

Fluorine-18 Radiolabelling and Photophysical Characteristics of Multimodal PET-Fluorescence Molecular Probes.

Positron emission tomography (PET)-fluorescence imaging is an emerging field of multimodality imaging seeking to attain synergy between the two techniques. The probes employed in PET-fluorescence imaging incorporate both a fluorophore and radioisotope which enable complementary information to be obtained from both imaging techniques via the administration of a single agent. Fluorine-18 is the most commonly used radioisotope in PET imaging and consequently many novel attempts to radiofluorinate various fluorophores have transpired over the past decade.

Rhenium(i) complexation-dissociation strategy for synthesising fluorine-18 labelled pyridine bidentate radiotracers.

A novel fluorine-18 method employing rhenium(i) mediation is described herein. The method was found to afford moderate to high radiochemical yields of labelled rhenium(i) complexes. Subsequent thermal dissociation of the complexes enabled the radiosynthesis of fluorine-18 labelled pyridine bidentate structures which could not be radiofluorinated hitherto.

[ F]Ethenesulfonyl Fluoride as a Practical Radiofluoride Relay Reagent.

Fluorine-18 is the most utilized radioisotope in positron emission tomography (PET), but the wide application of fluorine-18 radiopharmaceuticals is hindered by its challenging labelling conditions. As such, many potentially important radiotracers remain underutilized. Herein, we describe the use of [ F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres.

Perspectives on the Use of Liquid Extraction for Radioisotope Purification.

The reliable and efficient production of radioisotopes for diagnosis and therapy is becoming an increasingly important capability, due to their demonstrated utility in Nuclear Medicine applications. Starting from the first processes involving the separation of Tc from irradiated materials, several methods and concepts have been developed to selectively extract the radioisotopes of interest. Even though the initial methods were based on liquid-liquid extraction (LLE) approaches, the perceived difficulty in automating such processes has slowly moved the focus towards resin separation methods, whose basic chemical principles are often similar to the LLE ones in terms of chelators and phases.

[Cu]CuCl PET imaging reveals activity of Dextran-Catechin on tumor copper homeostasis.

Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [Cu]CuCl PET imaging protocol to monitor its effect on copper homeostasis in tumors.

Open-field PET: Simultaneous brain functional imaging and behavioural response measurements in freely moving small animals.

A comprehensive understanding of how the brain responds to a changing environment requires techniques capable of recording functional outputs at the whole-brain level in response to external stimuli. Positron emission tomography (PET) is an exquisitely sensitive technique for imaging brain function but the need for anaesthesia to avoid motion artefacts precludes concurrent behavioural response studies. Here, we report a technique that combines motion-compensated PET with a robotically-controlled animal enclosure to enable simultaneous brain imaging and behavioural recordings in unrestrained small animals.

Synthesis, bioconjugation and stability studies of [ F]ethenesulfonyl fluoride.

Fluorine-18 labelled prosthetic groups (PGs) are often necessary for radiolabelling sensitive biological molecules such as peptides and proteins. Several shortcomings, however, often diminish the final yield of radiotracer. In an attempt to provide higher yielding and operationally efficient tools for radiolabelling biological molecules, we describe herein the first radiochemical synthesis of [ F]ethenesulfonyl fluoride ([ F]ESF) and its Michael conjugation with amino acids and proteins.

Dose-on-demand production of diverse F-radiotracers for preclinical applications using a continuous flow microfluidic system.

Introduction: The production of F-radiotracers using continuous flow microfluidics is under-utilized due to perceived equipment limitations. We describe the dose-on-demand principle, whereby the back-to-back production of multiple, diverse F-radiotracers can be prepared on the same day, on the same microfluidic system using the same batch of [F]fluoride, the same microreactor, the same HPLC column and SPE cartridge to obtain a useful production yield.

Methods: [F]MEL050, [F]Fallypride and [F]PBR111 were radiolabeled with [F]fluoride using the Advion NanoTek Microfluidic Synthesis System.

A Fluorine-18 Radiolabeling Method Enabled by Rhenium(I) Complexation Circumvents the Requirement of Anhydrous Conditions.

Azeotropic distillation is typically required to achieve fluorine-18 radiolabeling during the production of positron emission tomography (PET) imaging agents. However, this time-consuming process also limits fluorine-18 incorporation, due to radioactive decay of the isotope and its adsorption to the drying vessel. In addressing these limitations, the fluorine-18 radiolabeling of one model rhenium(I) complex is reported here, which is significantly improved under conditions that do not require azeotropic drying.

Sulfur - fluorine bond in PET radiochemistry.

The importance of the sulfur-fluorine bond is starting to increase in modern medicinal chemistry literature. This is due to a better understanding of the stability and reactivity of this moiety depending on the various oxidation states of sulfur. Furthermore, several commercial reagents used for mild and selective fluorination of organic molecules are based on the known reactivity of S-F groups.

Design, synthesis and preliminary evaluation of (18)F-labelled 1,8-naphthyridin- and quinolin-2-one-3-carboxamide derivatives for PET imaging of CB2 cannabinoid receptor.

In the present work, we report the synthesis of new aryliodonium salts used as precursors of single-stage nucleophilic (18)F radiofluorination. The corresponding unlabelled fluorinated derivatives showed to be CB2 cannabinoid receptor specific ligands, with Ki values in the low nanomolar range and high CB2/CB1 selectivity. The radiolabelled compound [(18)F]CB91, was successfully formulated for in vivo administration, and its preliminary biodistribution was assessed with microPET/CT.

Optimisation of [11C]Raclopride production using a Synthra GPextent system.

The dopamine D2 receptor radiotracer [(11)C]Raclopride is used extensively in clinical and preclinical imaging. Currently, a wide range of methods to produce [(11)C]Raclopride have been developed using traditional vessel reactions as well as cartridge or captive solvent. This work reports the optimisation of the production of [(11)C]Raclopride using a Synthra GPextent, comparing various methods.

Optimization of nucleophilic ¹⁸F radiofluorinations using a microfluidic reaction approach.

Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost-effective optimization of new radiotracers.

Hardware and software modifications on the Advion NanoTek microfluidic platform to extend flexibility for radiochemical synthesis.

Microfluidic systems are currently receiving a lot of attention in the PET radiochemistry field, due to their demonstrated ability to obtain higher incorporation yields with reduced total processing time and using a decreased amount of precursors. The Advion NanoTek LF was the first commercial microfluidic system available for radiochemistry that allows basic parameter optimization to be performed. In this paper we report hardware and software modifications that would allow better performing procedures, higher product throughput and flexibility to utilize the system.

Microfluidics in radiopharmaceutical chemistry.

The increased demand for molecular imaging tracers useful in assessing and monitoring diseases has stimulated research towards more efficient and flexible radiosynthetic routes, including newer technologies. The traditional vessel-based approach suffers from limitations concerning flexibility, reagent mass needed, hardware requirements, large number of connections and valves, repetitive cleaning procedures and overall big footprint to be shielded from radiation. For these reasons, several research groups have started to investigate the application of the fast growing field of microfluidic chemistry to radiosynthetic procedures.

Radiochemistry on chip: towards dose-on-demand synthesis of PET radiopharmaceuticals.

We have developed an integrated microfluidic platform for producing 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) in continuous flow from a single bolus of radioactive isotope solution, with constant product yields achieved throughout the operation that were comparable to those reported for commercially available vessel-based synthesisers (40-80%). The system would allow researchers to obtain radiopharmaceuticals in a dose-on-demand setting within a few minutes. The flexible architecture of the platform, based on a modular design, can potentially be applied to the synthesis of other radiotracers that require a two-step synthetic approach, and may be adaptable to more complex synthetic routes by implementing additional modules.

Purification of 2-[18F]fluoro-2-deoxy-d-glucose by on-chip solid-phase extraction.

Microfluidic devices have shown great potential for the production of positron emission tomography (PET) radiotracers, but most devices have focused only on the synthesis step of the procedure, typically neglecting the other important steps such as [(18)F]fluoride pre-concentration and radiotracer purification that could equally benefit from miniaturisation. Here, we demonstrate the development of microfluidic modules for the purification of PET radiotracers, particularly 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG), via the use of on-chip solid-phase extraction (SPE). In these initial tests, the SPE modules were able to yield [(18)F]FDG with up to 90% radiochemical purity, and methods are proposed for further increasing this value.

[Translational perspectives in molecular imaging: methodological evolution and nanostructured materials].

Molecular imaging techniques play an increasingly important role in the deep understanding of pathologies. They represent a direct spotlight on the molecular correlates of diseases and can be used for assessing earlier the state of health and decide the treatment of each patient in a personalized way. This article will show the basis of several imaging techniques, and give examples on the application and development of molecular imaging tracers.

Dose-on-demand of diverse 18F-fluorocholine derivatives through a two-step microfluidic approach.

Introduction: The validation and confirmation of clinical usefulness of new and known positron emission tomography (PET) tracers require stable production routes and simple and robust radiochemical procedures. Microfluidic technologies are regarded as an approach that could allow an unprecedented flexibility and productivity in PET radiopharmaceutical research. In this work, we will show how a commercially available microfluidic system can be used for a sequential and repeatable radiosynthesis of three different fluorocholine analogues currently under investigation as tumor tracers.

On-chip pre-concentration and complexation of [¹⁸F]fluoride ions via regenerable anion exchange particles for radiochemical synthesis of Positron Emission Tomography tracers.

Microfluidic approaches have demonstrated a relevant impact on radiochemical reactions involving Positron Emission Tomography (PET) nuclides, due to shorter reaction times and smaller precursor quantities. However, little attention has been given to the integration of the initial pre-concentration and drying of radioactive [(18)F]fluoride ions, required for the labeling of radiotracer compounds. In this work we report the design, fabrication and implementation of a glass microfluidic device filled with recyclable anion exchange particles for the repeated recovery of [(18)F] and [(19)F]fluoride ions.

Development of an automated modular system for the synthesis of [11C]acetate.

Background: Carboxylation reactions offer a straightforward method for the synthesis of carbon-11 labelled carboxylic acids. Among these, the preparation of carbon-11 (C)-acetate is receiving increasing attention because of diagnostic applications in oncology in addition to its well-established use as a probe for myocardial oxidative metabolism. Although a number of dedicated modules are commercially available, the development of the synthesis on flexible platforms would be beneficial to widen the number of tracers, in particular for preclinical assessment and testing.