Mn-labelled Beta-cyclodextrin for Melanoma Imaging: A Proof-of-concept Preclinical Study.

Background/aim: As prostaglandin E2 (PGE2) and its receptors (EP2) are over-expressed on tumor cells and microenvironment, radiolabeled cyclodextrins targeting such biomolecules are valuable vector candidates in molecular cancer diagnostics. Using experimental melanoma models, we evaluated the in vivo imaging behavior of novel Manganese-52-labeled (Mn) randomly methylated beta-cyclodextrin ([Mn]Mn-DOTAGA-RAMEB) and compared it with the following well-established tumor-specific probes: melanocortin-1 receptor (MC1-R)-affine [Ga]Ga-DOTA-NAPamide and PGE2 selective [Ga]Ga-DOTAGA-RAMEB cyclodextrin.

Materials And Methods: Post-injection of [Ga]Ga-DOTA-NAPamide, [Ga]Ga-DOTAGA-RAMEB, and [Mn]Mn-DOTAGA-RAMEB into MC1-R positive B16F10 melanoma-bearing mice, tumor radio-pharmaceutical uptake was quantified in vivo and ex vivo using preclinical positron emission tomography (PET) and high-performance gamma counter.

Diagnosis of Melanoma with Cu-Labeled PET Tracer.

Until the recent years, substances containing radioactive Cu were strongly considered as potential positron-emitting radiopharmaceuticals for use in positron emission tomography (PET) applications; however, due to their suitably long half-life, and generator-independent and cost-effective production, they seem to be economically viable for human imaging. Since malignant melanoma (MM) is a major public health problem, its early diagnosis is a crucial contributor to long-term survival, which can be achieved using radiolabeled α-melanocyte-stimulating hormone analog NAPamide derivatives. Here, we report on the physicochemical features of a new CB-15aneN-based Cu(II) complex ([Cu(KFTGdiac)]) and the and characterization of its NAPamide conjugate.

[Mn]Mn-BPPA-Trastuzumab: A Promising HER2-Specific PET Radiotracer.

This study aimed to develop a novel radiotracer using trastuzumab and the long-lived [Mn]Mn isotope for HER2-targeted therapy selection and monitoring. A new Mn(II) chelator, BPPA, synthesized from a rigid bispyclen platform possessing a picolinate pendant arm, formed a stable and inert Mn(II) complex with favorable relaxation properties. BPPA was converted into a bifunctional chelator (BFC), conjugated to trastuzumab, and labeled with [Mn]Mn isotope.

Investigation of the Effect on the Albumin Binding Moiety for the Pharmacokinetic Properties of Ga-, Bi-, and Lu-Labeled NAPamide-Based Radiopharmaceuticals.

Although radiolabeled alpha-melanocyte stimulating hormone-analogue NAPamide derivatives are valuable melanoma-specific diagnostic probes, their rapid elimination kinetics and high renal uptake may preclude them from being used in clinical settings. We aimed at improving the pharmacokinetics of radiolabeled DOTA-NAPamide compounds by incorporating a 4-(p-iodo-phenyl)-butanoic acid (IPB) into the molecules. Followed by Ga-, Bi-, and Lu-labelling, the radiopharmaceuticals ([Ga]Ga-DOTA-IPB-NAPamide, [Bi]Bi-DOTA-IPB-NAPamide, [Lu]Lu-DOTA-IPB-NAPamide) were characterized in vitro.

In Vivo evaluation of newly synthesized Bi-conjugated alpha-melanocyte stimulating hormone (α-MSH) peptide analogues in melanocortin-1 receptor (MC1-R) positive experimental melanoma model.

Given the rising pervasiveness of melanocortin-1 receptor (MC1-R) positive melanoma malignum (MM) and pertinent metastases, radiolabelled receptor-affine alpha-melanocyte stimulating hormone-analogue (α-MSH analogue) imaging probes would be of crucial importance in timely tumor diagnostic assessment. Herein we aimed at investigating the biodistribution and the MM targeting potential of newly synthesized Bi-conjugated MC1-R specific peptide-based radioligands with the establishment of MC1-R overexpressing MM preclinical model. DOTA-conjugated NAP, -HOLD, -FOLD, -and MARSamide were labelled with Bi.

Rigid HOCTAPA derivatives as model chelators for the development of Bi(III)-based radiopharmaceuticals.

Octadentate ligands containing ethyl (HOCTAPA), cyclohexyl (HOCTAPA) or cyclopentyl (HOCTAPA) spacers were assessed as chelators for Bi(III)-based radiopharmaceuticals. The HOCTAPA chelator displays excellent properties, including Bi-nuclide radiolabelling under mild conditions, excellent stability in serum and in the presence of competing cations or HDTPA. The poor performance of HOCTAPA appears to be related to the stereochemical activity of the Bi(III) lone pair.

Therapeutic Performance Evaluation of Bi-Labelled Aminopeptidase N (APN/CD13)-Affine NGR-Motif ([Bi]Bi-DOTAGA-cKNGRE) in Experimental Tumour Model: A Treasured Tailor for Oncology.

Since NGR-tripeptides (asparagine-glycine-arginine) selectively target neoangiogenesis-associated Aminopeptidase N (APN/CD13) on cancer cells, we aimed to evaluate the in vivo tumour targeting capability of radiolabelled, NGR-containing, ANP/CD13-selective [Bi]Bi-DOTAGA-cKNGRE in CD13pos. HT1080 fibrosarcoma-bearing severe combined immunodeficient CB17 mice. 10 ± 1 days after cancer cell inoculation, positron emission tomography (PET) was performed applying [Ga]Ga-DOTAGA-cKNGRE for tumour verification.

AAZTA-Like Ligands Bearing Phenolate Arms as Efficient Chelators for Ga Labelling in vitro and in vivo.

The introduction of a phenolate pendant arm in place of an acetate on AAZTA- and DATA-like ligands resulted in hepta- and hexadentate chelators able to form Ga(III) complexes with thermodynamic stability and kinetic inertness higher than that of other Ga(III) complexes based on the parent 6-amino-6-methylperhydro-1,4-diazepine scaffold. In particular, the heptadentate AAZ3A-endoHB with a phenolate arm on an endocyclic N-atom shows a logK of 27.35 and a remarkable resistance to hydroxide coordination up to basic pH (pH>9).

In Vivo Preclinical Assessment of the VEGF Targeting Potential of the Newly Synthesized [Mn]Mn-DOTAGA-Bevacizumab Using Experimental Cervix Carcinoma Mouse Model.

Among humanized monoclonal antibodies, bevacizumab specifically binds to vascular endothelial growth factor A (VEGF-A). VEGF-A is an overexpressed biomarker in cervix carcinoma and is involved in the development and maintenance of tumor-associated neo-angiogenesis. The non-invasive positron emission tomography using radiolabeled target-specific antibodies (immuno-PET) provides the longitudinal and quantitative assessment of tumor target expression.

Cu-Labelled radiodiagnostics of melanoma with NAPamide-targeted radiopharmaceutical.

Malignant melanoma is a major public health problem with an increasing incidence and mortality in the Caucasian population due to its significant metastatic potential. The early detection of this cancer type by imaging techniques like positron emission tomography acts as an important contributor to the long-term survival. Based on literature data, the radio labelled alpha-MSH analog NAPamide molecule is an appropriate diagnostic tool for the detection of melanoma tumors.

The Synthesis and Preclinical Investigation of Lactosamine-Based Radiopharmaceuticals for the Detection of Galectin-3-Expressing Melanoma Cells.

Given that galectin-3 (Gal-3) is a β-galactoside-binding lectin promoting tumor growth and metastatis, it could be a valuable target for the treatment of Gal-3-expressing neoplasms. An aromatic group introduced to the C-3′ position of lactosamine increased its affinity for Gal-3. Herein, we aimed at developing a radiopharmaceutical for the detection of Gal-3 positive malignancies.

PET Probes for Preclinical Imaging of GRPR-Positive Prostate Cancer: Comparative Preclinical Study of [Ga]Ga-NODAGA-AMBA and [Sc]Sc-NODAGA-AMBA.

Gastrin-releasing peptide receptors (GRPR) are overexpressed in prostate cancer (PCa). Since bombesin analogue aminobenzoic-acid (AMBA) binds to GRPR with high affinity, scandium-44 conjugated AMBA is a promising radiotracer in the PET diagnostics of GRPR positive tumors. Herein, the GRPR specificity of the newly synthetized [Sc]Sc-NODAGA-AMBA was investigated in vitro and in vivo applying PCa PC-3 xenograft.

Boosting Bismuth(III) Complexation for Targeted α-Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA.

Targeted α therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide Bi shows favourable physical properties for this application, but the fast and stable chelation of this metal ion remains challenging. Herein, we demonstrate that the mesocyclic chelator AAZTA quickly coordinates Bi at room temperature, leading to a robust complex.

In vivo investigation of Gallium-68 and Bismuth-205/206 labeled beta cyclodextrin for targeted alpha therapy of prostaglandin E2 receptor-expressing tumors in mice.

Prostaglandin E2 (PGE2) molecule and its receptors play an important role in the development of malignancies and metastases therefore PGE2 may play a crucial role in the diagnosis and a new therapeutic target in the field of radionuclide therapy of PGE2-positive tumors. PGE2 form complexes with RAMEB (randomly-methylated-beta-cyclodextrin) with high affinity therefore the aim of this present study was to synthesize a PGE2-specific DOTAGA-RAMEB, which can be labeled with diagnostic and therapeutic isotopes also and binds to PGE2-positive tumors. DOTAGA-RAMEB was labeled with Ga and Bi radionuclides and their radiochemical purity (RCP%), partition coefficient (logP values), and in vitro and in vivo stability were determined.

Synthesis, Physicochemical, Labeling and In Vivo Characterization of Sc-Labeled DO3AM-NI as a Hypoxia-Sensitive PET Probe.

Hypoxia promotes angiogenesis, which is crucial for tumor growth, and induces malignant progression and increases the therapeutic resistance. Positron emission tomography (PET) enables the detection of the hypoxic regions in tumors using 2-nitroimidazole-based radiopharmaceuticals. We describe here a physicochemical study of the Sc(DO3AM-NI) complex, which indicates: (a) relatively slow formation of the Sc(DO3AM-NI) chelate in acidic solution; (b) lower thermodynamic stability than the reference Sc(DOTA); (c) however, it is substantially more inert and consequently can be regarded as an excellent Sc-binder system.

Methods for the Determination of Transition Metal Impurities in Cyclotron-Produced Radiometals.

Cyclotron-produced radiometals must be separated from the irradiated target and purified from other metal impurities, which could interfere with the radiolabeling process. We compared different chromatographic and colorimetric methods to determine the amount of transition metals in radioactive samples. Besides commercially available colorimetric tests, 4-(2-pyridylazo)resorcinol and xylenol orange were used as a non-selective metal reagents, forming water-soluble chelates with most of the transition metals immediately.

A New Oxygen Containing Pyclen-Type Ligand as a Manganese(II) Binder for MRI and Mn PET Applications: Equilibrium, Kinetic, Relaxometric, Structural and Radiochemical Studies.

A new pyclen-3,9-diacetate derivative ligand (H) was synthesized possessing an etheric O-atom opposite to the pyridine ring, to improve the dissociation kinetics of its Mn(II) complex (pyclen = 3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene).

Synthesis of Ga-Labeled cNGR-Based Glycopeptides and In Vivo Evaluation by PET Imaging.

Tumor hypoxia induces angiogenesis, which is required for tumor cell survival. The aminopeptidase N receptor (APN/CD13) is an excellent marker of angiogenesis since it is overexpressed in angiogenic blood vessels and in tumor cells. Asparagine-glycine-arginine (NGR) peptide analogs bind selectively to the APN/CD13 recepto, therefore, they are important vector molecules in the development of a PET radiotracer which is capable of detecting APN-rich tumors.

Synthesis of Novel, Dual-Targeting Ga-NODAGA-LacN-E[c(RGDfK)] Glycopeptide as a PET Imaging Agent for Cancer Diagnosis.

Radiolabeled peptides possessing an Arg-Gly-Asp (RGD) motif are widely used radiopharmaceuticals for PET imaging of tumor angiogenesis due to their high affinity and selectivity to αβ integrin. This receptor is overexpressed in tumor and tumor endothelial cells in the case of numerous cancer cell lines, therefore, it is an excellent biomarker for cancer diagnosis. The galectin-3 protein is also highly expressed in tumor cells and N-acetyllactosamine is a well-established ligand of this receptor.

Production of scandium radionuclides for theranostic applications: towards standardization of quality requirements.

In the frame of "precision medicine", the scandium radionuclides have recently received considerable interest, providing personalised adjustment of radiation characteristics to optimize the efficiency of medical care or therapeutic benefit for particular groups of patients. Radionuclides of scandium, namely scandium-43 and scandium-44 (Sc) as positron emitters and scandium-47 (Sc), beta-radiation emitter, seem to fit ideally into the concept of theranostic pair. This paper aims to review the work on scandium isotopes production, coordination chemistry, radiolabeling, preclinical studies and the very first clinical studies.

Social policy in the face of a global pandemic: Policy responses to the COVID-19 crisis in Central and Eastern Europe.

This article documents and compares the social policies that the governments in Central and Eastern Europe (CEE) implemented to combat the first wave of COVID-19 pandemic by focusing on Hungary, Lithuania, Poland and Slovakia. Our findings show that governments in all four countries reacted to the COVID-19 crisis by providing extensive protection for jobs and enterprises. Differences arise when it comes to solidaristic policy responses to care for the most vulnerable population, in which CEE countries show great variation.

Synthesis, radiolabeling, and pre-clinical evaluation of [Sc]Sc-AAZTA conjugate PSMA inhibitor, a new tracer for high-efficiency imaging of prostate cancer.

Purpose: The aim of this work was to demonstrate the suitability of AAZTA conjugated to PSMA inhibitor (B28110) labeled with scandium-44 as a new PET tracer for diagnostic imaging of prostate cancer.

Background: Nowadays, scandium-44 has received significant attention as a potential radionuclide with favorable characteristics for PET applications. A polyaminopolycarboxylate heptadentate ligand based on a 1,4-diazepine scaffold (AAZTA) has been thoroughly studied as chelator for Gd ions for MRI applications.

Shape and Size Tuning of Bi-Centered Polyoxopalladates: High Resolution Bi NMR and Bi Radiolabeling for Potential Pharmaceutical Applications.

We have discovered five bismuth(III)-containing polyoxopalladates (POPs) which were fully characterized by solution and solid-state physicochemical techniques: the cube-shaped [BiPdO(AsPh)] (BiPdAsL), [BiPdO(AsCHN)] (BiPdAsL), and [BiPdO(AsCHCOO)] (BiPdAsL) as well as the star-shaped [BiPdO(PO)H] (BiPdP) and [BiPdO(PPh)] (BiPdPL), respectively. The organically modified capping groups phenylarsonate, -azidophenylarsonate, and -carboxyphenylarsonate were chosen as the azido (-N) and carboxyl (-COOH) groups open up opportunities to covalently conjugate (via click reaction, amide coupling, etc.) with targeting vectors.