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Discussed are two picolinate appended bispidine ligands (3,7‐diazabicyclo[3.3.1]nonane derivatives) in comparison with an earlier described bis‐pyridine derivative, which are all known to strongly bind CuII. The radiopharmacological characterization of the two isomeric bispidine complexes includes quantitative labeling with 64CuII at ambient conditions with high radiochemical purities and yields (molar activities >200 MBq/nmol). Challenge experiments in presence of EDTA, cyclam, human serum and SOD demonstrate high stability and inertness of the 64Cu‐bispidine complexes. Biodistribution studies performed in Wistar rats indicate a rapid renal elimination for both 64Cu‐labeled chelates. The bispidine ligand with the picolinate group in N7 position was selected for further biological experiments, and its backbone was therefore substituted with a benzyl‐NCS group at C9. Two tumor target modules (TMs), targeting prostate stem cell antigen (PSCA), overexpressed in prostate cancer, and the fibroblast activation protein (FAP) in fibrosarcoma, were selected for thiourea coupling with the NCS‐functionalized ligand and lysine residues of TMs. Small animal PET experiments on tumor‐bearing mice showed specific accumulation of the 64Cu‐labeled TMs in PSCA‐ and FAP‐overexpressing tumors (standardized uptake value (SUV) for PC3: 2.7±0.6 and HT1080: 7.2±1.25) with almost no uptake in wild type tumors. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to millions of infections and deaths worldwide. As this virus evolves rapidly, there is a high need for treatment options that can win the race against new emerging variants of concern. Here, we describe a novel immunotherapeutic drug based on the SARS-CoV-2 entry receptor ACE2 and provide experimental evidence that it cannot only be used for (i) neutralization of SARS-CoV-2 in vitro and in SARSCoV- 2-infected animal models but also for (ii) clearance of virus-infected cells. For the latter purpose, we equipped the ACE2 decoy with an epitope tag. Thereby, we converted it to an adapter molecule, which we successfully applied in the modular platforms UniMAB and UniCAR for retargeting of either unmodified or universal chimeric antigen receptor-modified immune effector cells. Our results pave the way for a clinical application of this novel ACE2 decoy, which will clearly improve COVID-19 treatment. [ABSTRACT FROM AUTHOR]

Prostate specific membrane antigen (PSMA) is an excellent target for imaging and treatment of prostate carcinoma (PCa). Unfortunately, not all PCa cells express PSMA. Therefore, alternative theranostic targets are required. The membrane protein prostate stem cell antigen (PSCA) is highly overexpressed in most primary prostate carcinoma (PCa) cells and in metastatic and hormone refractory tumor cells. Moreover, PSCA expression positively correlates with tumor progression. Therefore, it represents a potential alternative theranostic target suitable for imaging and/or radioimmunotherapy. In order to support this working hypothesis, we conjugated our previously described anti-PSCA monoclonal antibody (mAb) 7F5 with the bifunctional chelator CHX-A″-DTPA and subsequently radiolabeled it with the theranostic radionuclide 177Lu. The resulting radiolabeled mAb ([177Lu]Lu-CHX-A″-DTPA-7F5) was characterized both in vitro and in vivo. It showed a high radiochemical purity (>95%) and stability. The labelling did not affect its binding capability. Biodistribution studies showed a high specific tumor uptake compared to most non-targeted tissues in mice bearing PSCA-positive tumors. Accordingly, SPECT/CT images revealed a high tumor-to-background ratios from 16 h to 7 days after administration of [177Lu]Lu-CHX-A″-DTPA-7F5. Consequently, [177Lu]Lu-CHX-A″-DTPA-7F5 represents a promising candidate for imaging and in the future also for radioimmunotherapy. [ABSTRACT FROM AUTHOR]

In this third in a series of reviews on adjuvant drug-assisted bone healing, further approaches aiming at influencing the healing process are discussed. Local and systemic modulation of bone metabolism is pursued with use of a number of drugs with completely different indications, which are characterized by a pleiotropic spectrum of action. These include drugs used to treat lipid disorders (HMG-CoA reductase inhibitors), hypertension (ACE inhibitors), osteoporosis (bisphosphonates), cancer (proteasome inhibitors) and others. Potential applications to enhance bone healing are discussed. [ABSTRACT FROM AUTHOR]

The treatment of critical-size bone defects following complicated fractures, infections or tumor resections is a major challenge. The same applies to fractures in patients with impaired bone healing due to systemic inflammatory and metabolic diseases. Despite considerable progress in development and establishment of new surgical techniques, design of bone graft substitutes and imaging techniques, these scenarios still represent unresolved clinical problems. However, the development of new active substances offers novel potential solutions for these issues. This work discusses therapeutic approaches that influence angiogenesis or hypoxic situations in healing bone and surrounding tissue. In particular, literature on sphingosine-1-phosphate receptor modulators and nitric oxide (NO•) donors, including bi-functional (hybrid) compounds like NO•-releasing cyclooxygenase-2 inhibitors, was critically reviewed with regard to their local and systemic mode of action. [ABSTRACT FROM AUTHOR]

Critical-size bone defects after compound fractures, infection, or tumor resection are challenging to treat. The same is true for fractures in patients with impaired bone healing due to metabolic diseases and cancer. Despite considerable progress over the last decade in surgical techniques, material design, and dedicated imaging approaches, these scenarios represent unsolved clinical problems. The high socioeconomic burden of such conditions justifies increasing interest in novel osteoinductive drugs for adjuvant therapeutic approaches. There is an increasing body of experimental and clinical literature on potentially promising effects of growth factors, anti-resorptive, and anabolic agents. The true clinical efficacy of these, however, is discussed controversially. Therefore, we aimed to critically examine the hypothesis that targeted adjuvant therapies have the potential to enhance bone regeneration in critical-size bone defects and under systemic conditions that impair bone healing. This first approach to the topic deals with small molecule drugs and compounds that influence the immune response and inflammatory processes. In particular, literature reporting on selective cyclooxygenase-2 inhibitors has been reviewed with respect to their local and systemic mode of action and to stimulate further research on bone healing under critical conditions. [ABSTRACT FROM AUTHOR]

Radiolabeled α‐melanocyte‐stimulating hormone (α‐MSH) derivatives have a high potential for diagnosis and treatment of melanoma, because of high specificity and binding affinity to the melanocortin‐1 receptor (MC1R). Hence, the α‐MSH‐derived peptide NAP‐NS1 with a β‐Ala linker (ε‐Ahx‐β‐Ala‐Nle‐Asp‐His‐D‐Phe‐Arg‐Trp‐Gly‐NH2) was conjugated to different chelators: either to NOTA (p‐SCN‐Bn‐1,4,7‐triazacyclononane‐1,4,7‐triacetic acid), to a hexadentate bispidine carbonate derivative (dimethyl‐9‐(((4‐nitrophenoxy)carbonyl)oxy)‐2,4‐di(pyridin‐2‐yl)‐3,7‐bis(pyridin‐2‐ylmethyl)‐3,7‐diazabicyclo[3.3.1]nonane‐1,5‐dicarboxylate), or to DMPTACN (p‐SCN‐Ph‐bis(2‐pyridyl‐methyl)‐1,4,7‐triaza‐cyclononane), labeled with 64Cu, and investigated in terms of radiochemical and radiopharmacological properties. For the three 64Cu‐labeled conjugates negligible transchelation, suitable buffer and serum stability, as well as appropriate water solubility, was determined. The three conjugates exhibited high binding affinity (low nanomolar range) in murine B16F10, human MeWo, and human TXM13 cells. The Bmax values of [64Cu]Cu‐bispidine‐NAP‐NS1 ([64Cu]Cu‐2) and [64Cu]Cu‐DMPTACN‐NAP‐NS1 ([64Cu]Cu‐3) were higher than those of [64Cu]Cu‐NOTA‐NAP‐NS1 ([64Cu]Cu‐1), implying that different charged chelate units might have an impact on binding capacity. Preliminary in vivo biodistribution studies suggested the main excretion pathway of [64Cu]Cu‐1 and [64Cu]Cu‐3 to be renal, while that of [64Cu]Cu‐2 seemed to be both renal and hepatobiliary. An initial moderate uptake in the kidney decreased clearly after 60 minutes. All three 64Cu‐labeled conjugates should be considered for further in vivo investigations using a suitable xenograft mouse model. [ABSTRACT FROM AUTHOR]

An O‐methyltyrosine‐containing azadipeptide nitrile was synthesised and investigated for its inhibitory activity towards cathepsins L, S, K, and B. Labelling with carbon‐11 was accomplished by reaction of the corresponding phenolic precursor with [11C]methyl iodide starting from cyclotron‐produced [11C]methane. Radiopharmacological evaluation of the resulting radiotracer in a mouse xenograft model derived from a mammary tumour cell line by small animal PET imaging indicates tumour targeting with complex pharmacokinetics. Radiotracer uptake in the tumour region was considerably lower under treatment with the nonradioactive reference compound and the epoxide‐based irreversible cysteine cathepsin inhibitor E64. The in vivo behaviour observed for this radiotracer largely confirms that of the corresponding 18F‐fluoroethylated analogue and suggests the limited suitability of azadipeptide nitriles for the imaging of tumour‐associated cysteine cathepsins despite target‐mediated uptake is evidenced. [ABSTRACT FROM AUTHOR]