Molecular or personalised medicine is the future of patient management and healthcare, and molecular imaging plays a key role towards this goal. However, amongst molecular imaging techniques, no single modality is perfect and sufficient to gain all the necessary information. For instance, optical fluorescence imaging is difficult to quantify--especially in tissue more than a few millimetres in depth within a subject; magnetic resonance imaging (MRI) has superb resolution but low sensitivity and positron emission tomography (PET) has very high sensitivity but poor resolution. The combination of multiple molecular imaging techniques can therefore offer synergistic advantages over any modality alone. However, the problem cannot be solved by simply adding two different classes of imaging probes together, unless they happen to have identical pharmacodynamic properties. Therefore, multi-modal contrast agents or imaging probes have been developed to solve this problem. Despite the great wealth of information that such probes can provide, their development is far from trivial and represents an important challenge to synthetic chemists. In this feature article, we provide an overview of recent findings in the synthesis, evaluation and application of dual-modality molecular imaging probes.
Abstract:The evaluation and selection of the most appropriate catalyst for a chemical transformation is an important process in many areas of synthetic chemistry. Conventional catalyst screening involving batch reactor systems can be both time-consuming and expensive, resulting in a large number of individual chemical reactions. Continuous flow microfluidic reactors are increasingly viewed as a powerful alternative format for reacting and processing larger numbers of small-scale reactions in a rapid, more controlled and safer fashion. In this study we demonstrate the use of a planar glass microfluidic reactor for performing the three-component palladium-catalysed aminocarbonylation reaction of iodobenzene, benzylamine and carbon monoxide to form N-benzylbenzamide, and screen a series of palladium catalysts over a range of temperatures. N-Benzylbenz-A C H T U N G T R E N N U N G amide product yields for this reaction were found to be highly dependent on the nature of the catalyst and reaction temperature. The majority of catalysts gave good to high yields under typical flow conditions at high temperatures (150 8C), however the palladium(II) chloride-Xantphos complex [PdCl 2 A C H T U N G T R E N N U N G (Xantphos)] proved to be far superior as a catalyst at lower temperatures (75-120 8C). The utilised method was found to be an efficent and reliable way for screening a large number of palladium-catalysed carbonylation reactions and may prove useful in screening other gas/liquid phase reactions.
Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal–organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2–4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.
A model palladium-mediated carbonylation reaction synthesizing N-benzylbenzamide from iodobenzene and benzylamine was used to investigate the potential of four N-heterocyclic carbenes (N, III) and N,N 0 -bis(1-adamantyl)imidazolium chloride (IV)) to act as supporting ligands in combination with Pd 2 (dba) 3 . Their activities were compared with other Pd-diphosphine complexes after reaction times of 10 and 120 min. Pd 2 (dba) 3 and III were the best performing after 10 min reaction (20%) and was used to synthesize radiolabelled [11 C]N-benzylbenzamide in good radiochemical yield (55%) and excellent radiochemical purity (99%). A Cu(Tp*) complex was used to trap the typically unreactive and insoluble [ 11 C]CO which was then released and reacted via the Pd-mediated carbonylation process. Potentially useful side products [11 C]N,N 0 -dibenzylurea and [ 11 C]benzoic acid were also observed. Increased amounts of [ 11 C]N,N 0 -dibenzylurea were yielded when PdCl 2 was the Pd precursor. Reduced yields of [ 11 C]benzoic acid and therefore improved RCP were seen for III/Pd 2 (dba) 3 over commonly used dppp/Pd 2 (dba) 3 making it more favourable in this case.
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