Modular Medical Imaging Agents Based on Azide-Alkyne Huisgen Cycloadditions:Synthesis and Pre-Clinical Evaluation of(18)F-Labeled PSMA-Tracers for Prostate Cancer Imaging

Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide–alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide–alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre-clinical in vivo evaluation of fluorine-18- labeled PSMA-targeting ‘F-PSMA-MIC’ radiotracers (t1/2=109.7 min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [68Ga]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents

Fighting Malaria:Structure-Guided Discovery of Nonpeptidomimetic Plasmepsin Inhibitors

Plasmepsins (Plms) are aspartic proteases involved in the degradation of human hemoglobin by Plasmodium falciparum. Given that the parasite needs the resulting amino acid building blocks for its growth and development, plasmepsins are an important antimalarial drug target. Over the past decade, tremendous progress has been achieved in the development of inhibitors of plasmepsin using two strategies: structure-based drug design (SBDD) and structure-based virtual screening (SBVS). Herein, we review the inhibitors of Plms I-IV developed by SBDD or SBVS with a particular focus on obtaining selectivity versus the human Asp proteases cathepsins and renin and activity in cell-based assays. By use of SBDD, the flap pocket of Plm II has been discovered and constitutes a convenient handle to obtain selectivity. In SBVS, activity against Plms I-IV and selectivity versus cathepsins are not always taken into account. A combination of SBVS, SBDD, and molecular dynamics simulations opens up opportunities for future design cycles

Synthesis and preclinical evaluation of 2-(2-furanyl)-7-[2-[4-[4-(2-[11C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine ([11C]Preladenant) as a PET tracer for the imaging of cerebral adenosine A2A receptors

2-(2-Furanyl)-7-[2-[4-[4-(2-[C-11]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine [(11)C]-3 ([C-11]Preladenant) was developed for mapping cerebral adenosine A2A receptors (A2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiography (ARG) experiments. Regional brain uptake of [C-11]-3 was consistent with known A(2A)Rs distribution, with highest uptake in striatum. The results indicate that [C-11]-3 has favorable brain kinetics and exhibits suitable characteristics as an A(2A)R PET tracer

Evaluation of an evidence-based guidance on the reduction of physical restraints in nursing homes: a cluster-randomised controlled trial [ISRCTN34974819]

<p>Abstract</p> <p>Background</p> <p>Physical restraints are regularly applied in German nursing homes. Their frequency varies substantially between centres. Beneficial effects of physical restraints have not been proven, however, observational studies and case reports suggest various adverse effects. We developed an evidence-based guidance on this topic. The present study evaluates the clinical efficacy and safety of an intervention programme based on this guidance aimed to reduce physical restraints and minimise centre variations.</p> <p>Methods/Design</p> <p>Cluster-randomised controlled trial with nursing homes randomised either to the intervention group or to the control group with standard information. The intervention comprises a structured information programme for nursing staff, information materials for legal guardians and residents' relatives and a one-day training workshop for nominated nurses. A total of 36 nursing home clusters including approximately 3000 residents will be recruited. Each cluster has to fulfil the inclusion criteria of at least 20% prevalence of physical restraints at baseline. The primary endpoint is the number of residents with at least one physical restraint at six months. Secondary outcome measures are the number of falls and fall-related fractures.</p> <p>Discussion</p> <p>If successful, the intervention should be implemented throughout Germany. In case the intervention does not succeed, a three-month pre-post-study with an optimised intervention programme within the control group will follow the randomised trial.</p> <p>Trial registration</p> <p>ISRCTN34974819</p

Synthesis and Preclinical Evaluation of 2‑(2-Furanyl)-7-[2-[4-[4-(2‑[¹¹C]methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7<i>H</i>‑pyrazolo[4,3‑<i>e</i>][1,2,4]triazolo[1,5‑<i>c</i>]pyrimidine-5-amine ([¹¹C]Preladenant) as a PET Tracer for the Imaging of Cerebral Adenosine A_2A Receptors

2-(2-Furanyl)-7-[2-[4-[4-(2-[¹¹C]­methoxyethoxy)­phenyl]-1-piperazinyl]­ethyl]­7<i>H</i>-pyrazolo­[4,3-<i>e</i>]­[1,2,4]­triazolo­[1,5-<i>c</i>]­pyrimidine-5-amine [¹¹C]-<b>3</b> ([¹¹C]­Preladenant) was developed for mapping cerebral adenosine A_2A receptors (A_2ARs) with PET. The tracer was synthesized in high specific activity and purity. Tissue distribution was studied by PET imaging, ex vivo biodistribution (BD), and in vitro autoradiography (ARG) experiments. Regional brain uptake of [¹¹C]-<b>3</b> was consistent with known A_2ARs distribution, with highest uptake in striatum. The results indicate that [¹¹C]-<b>3</b> has favorable brain kinetics and exhibits suitable characteristics as an A_2AR PET tracer