Development Of Radiopharmaceuticals Research Articles

Bispidine-based Ligands as Bifunctional Chelators for Radiopharmaceuticals

Abstract: Novel bispidine skeleton has been extensively designed as bifunctional chelators (BFCs) for their special stereochemical structure and variable dentate numbers. Bispidine-based ligands (BBLs) as BFCs generally integrate the benefits of conventional acyclic and macrocyclic BFCs, demonstrating exceptional radiolabeling kinetics, thermodynamic stability and kinetic inertness for their metal complexes. The accessible inherent spatial asymmetry in bispidine skeleton is well-suited for Jahn-Teller active metal ions, notably Cu(II). Currently, BBLs have already been studied to coordinate with radionuclides such as 52Mn, 64/67Cu, 68Ga, 111In, 133La, 177Lu, 212Pb, 212/213Bi, and 225Ac for radiopharmaceuticals application. Among them, the 64Cu, 52Mn, 111In, 177Lu, and 225Ac complexes with BBLs have particularly made significant research progress. In this review, we introduce the synthesis of BBLs and their applications in chelating the above five metallic radionuclides for the development of radiopharmaceuticals are discussed.

Chemistry of Antimony in Radiopharmaceutical Development: Unlocking the Theranostic Potential of Sb Isotopes.

Antimony-119 (119Sb) holds promise for radiopharmaceutical therapy (RPT), emitting short-range Auger and conversion electrons that can deliver cytotoxic radiation on a cellular level. While it has high promise theoretically, experimental validation is necessary for 119Sb in vivo applications. Current 119Sb production and separation methods face robustness and compatibility challenges in radiopharmaceutical synthesis. Limited progress in chelator development hampers targeted experiments with 119Sb. This review compiles literature on the toxicological, biodistribution and redox properties of Sb, along with existing Sb complexes, evaluating their suitability for radiopharmaceuticals. Sb(III) is suggested as the preferred oxidation state for radiopharmaceutical elaboration due to its stability in vivo and lack of skeletal uptake. While Sb complexes with both hard and soft donor atoms can be achieved, Sb thiol complexes offer enhanced stability and compatibility with the desired Sb(III) oxidation state. For 119Sb to find application in RPT, scientists need to make discoveries and advancements in the areas of isotope production, and radiometal chelation. This review aims to guide future research towards harnessing the therapeutic potential of 119Sb in RPT.

Medicinal (Radio)Chemistry: Building Radiopharmaceuticals for the Future.

Radiopharmaceuticals are increasingly playing a leading role in diagnosing, monitoring, and treating disease. In comparison with conventional pharmaceuticals, the development of radiopharmaceuticals does follow the principles of medicinal chemistry in the context of imaging-altered physiological processes. The design of a novel radiopharmaceutical has several steps similar to conventional drug discovery and some particularity. In the present work, we revisited the insights of medicinal chemistry in the current radiopharmaceutical development giving examples in oncology, neurology, and cardiology. In this regard, we overviewed the literature on radiopharmaceutical development to study overexpressed targets such as prostate-specific membrane antigen and fibroblast activation protein in cancer; β-amyloid plaques and tau protein in brain disorders; and angiotensin II type 1 receptor in cardiac disease. The work addresses concepts in the field of radiopharmacy with a special focus on the potential use of radiopharmaceuticals for nuclear imaging and theranostics.

The Historical Background of Quality Assurance at Laboratório de Imagem Molecular of the Centro de Desenvolvimento da Tecnologia Nuclear

The Centro de Desenvolvimento da Tecnologia Nuclear has a small animals positron emission tomograph in its Laboratório de Imagem Molecular. This equipment, the GE HealthCare LabPET SOLO 4 model, is widely used in preclinical studies related to the development of new radiopharmaceuticals or novel applications of conventional radiopharmaceuticals. The “PET Image Quality” subproject, integrated into the Centro de Desenvolvimento da Tecnologia Nuclear multi-year planning for 2018-2022, proposed actions involving quality assurance and human resources development for the laboratory. This work aims to consolidate the historical trajectory of Quality Assurance at Laboratório de Imagem Molecular of the Centro de Desenvolvimento da Tecnologia Nuclear. A search for documents related to the laboratory was conducted in the institutional quality system, called d-Qualidade, while a search for the curricula vitae of laboratory researchers was performed on the Plataforma Lattes, with the purpose of identifying the main products generated related to the Quality theme in the laboratory. The scientific production of the laboratory team demonstrates its pioneering role in Brazil in developing studies about the Quality Management applied to the small animals positron emission tomogragh. The laboratory history in the field of Quality Management emphasizes its national prominence and reveals the group's commitment over the past decade to significant technical/scientific production.

Cisplatin-Containing Combinations Associate with Survival in Women from Appalachian Kentucky with Metastatic, Persistent, or Recurrent Uterine Cervix Cancer.

Background: Prior preclinical studies showed promising antitumor activity and an acceptable safety profile associated with radiopharmaceuticals for patients with metastatic, persistent, or recurrent uterine cervix cancers. Whether the addition of a radiopharmaceutical to chemotherapy would significantly increase progression-free survival in such patients is untested. Our retrospective study sought to associate the line of treatment and progression-free survival as benchmarks for next-generation radiopharmaceutical development. Methods: We grouped metastatic, persistent, or recurrent uterine cervix cancer patients not amenable to curable surgery or radiotherapy between 2002 and 2023 by the line of doublet, triplet, and quadruplet chemotherapy or another intervention. After the first-line treatment, patients were monitored for radiographic progression every three months for up to three years. The primary endpoints were the first and any second or third progression-free survival intervals. Results: A total of 127 patients contributed demographic, tumor, line of treatment, and outcome data with a median follow-up of 18 months (25-75% interquartile range: 9 to 37 months). After the first-line treatment, 113 patients had local or distant progression or died from any cause, most often death from the disease (67%). Median progression-free survivals were 5.5 months (95% confidence interval: 4.8-6.0 months), 5.3 months (95% confidence interval: 4.5-6.3 months), and 3.0 months (95% confidence interval: 2.1-3.7 months) for the first-, second-, and third-line treatments, respectively. For a first-line cisplatin-containing regimen, the median progression-free survival was 6.5 months (95% confidence interval: 5.5-7.7 months). Conclusions: This study highlights the limited efficacy of current treatments for metastatic, persistent, or recurrent uterine cancer patients. A five-month progression-free survival might serve as a benchmark for the development of novel therapies in clinical efficacy trials, such as radiopharmaceuticals.

186Re]Re- and [99mTc]Tc-Tricarbonyl Metal Complexes with 1,4,7-Triazacyclononane-Based Chelators Bearing Amide, Alcohol, or Ketone Pendent Groups.

1,4,7-Triazacyclononane (TACN)-based chelators, such as NOTA and NODAGA, have shown great promise as bifunctional chelators for [M(CO)3]+ cores (M = 99mTc and 186Re) in radiopharmaceutical development. Previous investigations of TACN-based chelators bearing pendent acid and ester arms demonstrated the important role the pendent arms have in successful coordination of the [M(CO)3]+ core with the TACN backbone nitrogens. In this work, we introduce three TACN-based bifunctional chelators bearing amide, alcohol, and ketone pendent arms and evaluate their (radio)labeling efficiency with the [M(CO)3]+ core as well as the in vitro stability and hydrophilicity of the resulting radiometal complexes. Following their synthesis and characterization, the amide (2) and alcohol (3) chelators were successfully labeled with the [M(CO)3]+ cores (M = natRe, 99mTc, and 186Re), while the ketone (4) was not successfully labeled. Radiometal complexes M-2 and M-3 demonstrated hydrophilic character in logD7.4 studies as well as excellent stability in phosphate-buffered saline (pH 7.4), l-histidine, l-cysteine, and rat serum at 37 °C through 24 h. While the hydrophilicity and stability of these radiocomplexes are attractive, future TACN chelator design modifications to increase radiolabeling yields under milder reaction conditions would improve their potential for use in development of [M(CO)3]+ radiopharmaceuticals.

Quantitative SPECT imaging of 155Tb and 161Tb for preclinical theranostic radiopharmaceutical development.

Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, 155Tb (t1/2 = 5.32 d) and 161Tb (t1/2 = 6.89 d) have been proposed as a theranostic pair for their respective applications in single photon emission computed tomography (SPECT) imaging and targeted beta therapy. Our study assessed the performance of preclinical quantitative SPECT imaging with 155Tb and 161Tb. A hot rod resolution phantom with rod diameters ranging between 0.85 and 1.70mm was filled with either 155Tb (21.8 ± 1.7 MBq/mL) or 161Tb (23.6 ± 1.9 MBq/mL) and scanned with the VECTor preclinical SPECT/CT scanner. Image performance was evaluated with two collimators: a high energy ultra high resolution (HEUHR) collimator and an extra ultra high sensitivity (UHS) collimator. SPECT images were reconstructed from photopeaks at 43.0keV, 86.6keV, and 105.3keV for 155Tb and 48.9keV and 74.6keV for 161Tb. Quantitative SPECT images of the resolution phantoms were analyzed to report inter-rod contrast, recovery coefficients, and contrast-to-noise metrics. Quantitative SPECT images of the resolution phantom established that the HEUHR collimator resolved all rods for 155Tb and 161Tb, and the UHS collimator resolved rods ≥ 1.10mm for 161Tb and ≥ 1.30mm for 155Tb. The HEUHR collimator maintained better quantitative accuracy than the UHS collimator with recovery coefficients up to 92%. Contrast-to-noise metrics were also superior with the HEUHR collimator. Both 155Tb and 161Tb demonstrated potential for applications in preclinical quantitative SPECT imaging. The high-resolution collimator achieves < 0.85mm resolution and maintains quantitative accuracy in small volumes which is advantageous for assessing sub organ activity distributions in small animals. This imaging method can provide critical quantitative information for assessing and optimizing preclinical Tb-radiopharmaceuticals.

Assessment of chromatography separation parameters in the quality control of copper-64-labeled neurotensin-like peptides

In recent years, research on the Cu-64 effects on malignant tumours has increased, leading to the development of radiopharmaceuticals with higher selectivity, aiming to target tumour cells while preserving healthy body cells. This work aims to assess the quality of two DOTA-derivatized neuropeptides, NMN and NT (8-13) radiolabelled with Cu-64. An improved analytical radio-HPLC method was developed to evaluate the radiochemical purity and stability. The radiochemical purity is > 99.95% for both 64Cu-DOTA-NMN and 64Cu-DOTA-NT (8-13), the radiolabelled molecules being stable for 72 h after synthesis.

TSPO Radioligands for Neuroinflammation: An Overview.

The translocator protein (TSPO) is predominately localized on the outer mitochondrial membrane in steroidogenic cells. In the brain, TSPO expression, low under normal conditions, results upregulated in response to glial cell activation, that occurs in neuroinflammation. As a consequence, TSPO has been extensively studied as a biomarker of such conditions by means of TSPO-targeted radiotracers. Although [11C]-PK11195, the prototypical TSPO radioligand, is still widely used for in vivo studies, it is endowed with severe limitations, mainly low sensitivity and poor amenability to quantification. Consequently, several efforts have been focused on the design of new radiotracers for the in vivo imaging of TSPO. The present review will provide an outlook on the latest advances in TSPO radioligands for neuroinflammation imaging. The final goal is to pave the way for (radio)chemists in the future design and development of novel effective and sensitive radiopharmaceuticals targeting TSPO.

3312: Challenges in radiopharmaceutical development and evaluation

3312: Challenges in radiopharmaceutical development and evaluation

Development of 52Mn Labeled Trastuzumab for Extended Time Point PET Imaging of HER2

PurposeDue to their long circulation time in the blood, monoclonal antibodies (mAbs) such as trastuzumab, are usually radiolabeled with long-lived positron emitters for the development of agents for Positron Emission Tomography (PET) imaging. Manganese-52 (52Mn, t1/2 = 5.6 d, β+ = 29.6%, E(βave) = 242 keV) is suitable for imaging at longer time points providing a complementary technique to Zirconium-89 (89Zr, t1/2 = 3.3 d, β+ = 22.7%, E(βave) = 396 keV)) because of its long half-life and low positron energy. To exploit these properties, we aimed to investigate suitable bifunctional chelators that could be readily conjugated to antibodies and labeled with 52Mn under mild conditions using trastuzumab as a proof-of-concept.ProceduresTrastuzumab was incubated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 1-Oxa-4,7,10-tetraazacyclododecane-5-S-(4-isothiocyantobenzyl)-4,7,10-triacetic acid (p-SCN-Bn-Oxo-DO3A), and 3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (p-SCN-Bn-PCTA) at a tenfold molar excess. The immunoconjugates were purified, combined with [52Mn]MnCl2 at different ratios, and the labeling efficiency was assessed by iTLC. The immunoreactive fraction of the radiocomplex was determined through a Lindmo assay. Cell studies were conducted in HER2 + (BT474) and HER2- (MDA-MB-468) cell lines followed by in vivo studies.ResultsTrastuzumab-Oxo-DO3A was labeled within 30 min at 37 °C with a radiochemical yield (RCY) of 90 ± 1.5% and with the highest specific activity of the chelators investigated of 16.64 MBq/nmol. The labeled compound was purified with a resulting radiochemical purity of > 98% and retained a 67 ± 1.2% immunoreactivity. DOTA and PCTA immunoconjugates resulted in < 50 ± 2.5% (RCY) with similar specific activity. Mouse serum stability studies of [52Mn]Mn-Oxo-DO3A-trastuzumab showed 95% intact complex for over 5 days. Cell uptake studies showed higher uptake in HER2 + (12.51 ± 0.83% /mg) cells compared to HER2- (0.85 ± 0.10%/mg) cells. PET images of mice bearing BT474 tumors showed high tumor uptake that was consistent with the biodistribution (42.02 ± 2.16%ID/g, 14 d) compared to MDA-MB-468 tumors (2.20 ± 0.80%ID/g, 14 d). Additionally, both models exhibited low bone uptake of < 1% ID/g.ConclusionThe bifunctional chelator p-SCN-Bn-Oxo-DO3A is promising for the development of 52Mn radiopharmaceuticals as it was easily conjugated, radiolabeled at mild conditions, and illustrated stability for a prolonged duration both in vitro and in vivo. High-quality PET/CT images of [52Mn]Mn-Oxo-DO3A-trastuzumab were obtained 14 d post-injection. This study illustrates the potential of [52Mn]Mn-Oxo-DO3A for the evaluation of antibodies using PET imaging.

18 F-Fluorination of Nitroimidazolyl-Containing Sultone: A Direct Access to a Highly Hydrophilic Radiotracer for High-Performance Positron Emission Tomography Imaging of Hypoxia.

Hypoxia, characterized by nonphysiological levels of oxygen tension, is a key phenomenon common to the majority of malignant tumors with poor prognosis. Many efforts have been made to develop hypoxia imaging for diagnosis, staging, and monitoring of diseases, as well as for evaluating therapies. PET Imaging using 18F-fluoronitroimidazoles (i.e., [18F]FMISO as a lead radiotracer) has demonstrated potential for clinical investigations, but the poor contrast and prolonged acquisition times (>2.5 h) strongly limit its accuracy and routine developments. Here, we report an original [18F]fluoronitroimidazole bearing a sulfo group ([18F]FLUSONIM) that displays highly hydrophilic properties and rapid clearance, providing high-performance hypoxia specific PET imaging. We describe the synthesis and radiosynthesis of [18F]FLUSONIM, its in vivo preclinical evaluation by PET imaging in healthy rats and a rhabdomyosarcoma rat model, as well as its radiometabolization and histological studies. [18F]FLUSONIM was prepared in a single step by high yielding radiofluorination of a sultone precursor, highlighting the advantages of this new radiolabeling approach not yet explored for radiopharmaceutical development. PET imaging experiments were conducted by systematically comparing [18F]FLUSONIM to [18F]FMISO as a reference. The overall results unequivocally demonstrate that the developed radiopharmaceutical meets the criteria of an ideal candidate for hypoxia PET imaging-rapid and efficient radiosynthesis, total stability, exclusive urinary elimination, high specificity for hypoxic regions, unprecedented tumor/background ratios, short acquisition delays (<60 min), and promising potential for further preclinical and clinical applications.

Scalability study on [133La]LaCl3 production with a focus on potential clinical applications

BackgroundIn recent years, targeted alpha therapy has gained importance in the clinics, and in particular, the alpha-emitter 225Ac plays a fundamental role in this clinical development. Nevertheless, depending on the chelating system no real diagnostic alternative has been established which shares similar chemical properties with this alpha-emitting radionuclide. In fact, the race to launch a diagnostic radionuclide to form a matched pair with 225Ac is still open, and 133La features attractive radiation properties to claim this place. However, in order to enable its translation into clinical use, upscaling of the production of this PET radionuclide is needed.ResultsA study on optimal irradiation parameters, separation conditions and an exhaustive product characterization was carried out. In this framework, a proton irradiation of 2 h, 60 µA and 18.7 MeV produced 133La activities of up to 10.7 GBq at end of bombardment. In addition, the performance of four different chromatographic resins were tested and two optimized purification methods presented, taking approximately 20 min with a 133La recovery efficiencies of over 98%, decay corrected. High radionuclide purity and apparent molar activity was proved, of over 99.5% and 120 GBq/µmol, respectively, at end of purification. Furthermore, quantitative complexation of PSMA-617 and mcp-M-PSMA were obtained with molar activities up to 80 GBq/µmol. In addition, both 133La-radioconjugates offered high stability in serum, of over (98.5 ± 0.3)% and (99.20 ± 0.08)%, respectively, for up to 24 h. A first dosimetry estimation was also performed and it was calculated that an 133La application for imaging with between 350 and 750 MBq would only have an effective dose of 2.1–4.4 mSv, which is comparable to that of 18F and 68Ga based radiopharmaceuticals.ConclusionsIn this article we present an overarching study on 133La production, from the radiation parameters optimization to a clinical dose estimation. Lanthanum-133 activities in the GBq range could be produced, formulated as [133La]LaCl3 with high quality regarding radiolabeling and radionuclide purity. We believe that increasing the 133La availability will further promote the development of radiopharmaceuticals based on macropa or other chelators suitable for 225Ac.Graphical abstract

PET imaging of [52 Mn]Mn-DOTATATE and [52 Mn]Mn-DOTA-JR11.

Manganese-52 is gaining interest as an isotope for PET imaging due to its desirable decay and chemical properties for radiopharmaceutical development. Somatostatin receptor 2 (SSTR2) is significantly overexpressed by neuroendocrine tumors (NETs) and is an important target for nuclear imaging and therapy. As an agonist, [68Ga]Ga-DOTATATE has demonstrated significant internalization upon interaction with receptor ligands, whereas [68Ga]Ga-DOTA-JR11(as an antagonist) exhibits limited internalization but better pharmacokinetics and increased tumor uptake. The goal of this study was to label both DOTATATE and DOTA-JR11 peptides with 52Mn in high radiochemical yields (RCY) and sufficient specific activity. A comparison of these two compounds was performed in in vitro and in vivo studies in animals with somatostatin receptor-positive xenografts to characterize differences in cell, tumor, and tissue uptake. Radiolabeling of DOTATATE and DOTA-JR11 was carried out by combining varying concentrations of the peptides with [52Mn]MnCl2. In vitro stability of the radiotracers was determined in mouse serum. In vitro cell uptake and internalization assays were performed in SSTR2 + AR42J cells and negative controls. In vivo biodistribution and longitudinal PET imaging was evaluated in mice bearing AR42J tumors. Both [52Mn]Mn-DOTATATE and [52Mn]Mn-DOTA-JR11showed affinity for SSTR2 in AR42J cells. However, the uptake of [52Mn]Mn-DOTATATE was higher (11.95 ± 0.71%/ mg) compared to [52Mn]Mn-DOTA-JR11 (7.31 ± 0.38%/ mg) after 2 h incubation. After 4 h incubation, 53.13 ± 1.83% of the total activity of [52Mn]Mn-DOTATATE was internalized, whereas only 20.85 ± 0.59% of the total activity of [52Mn]Mn-DOTA-JR11 was internalized. The PET images revealed similar biodistribution results, with [52Mn]Mn-DOTATATE showing a significant tumor uptake of 11.16 ± 2.97% ID/g, while [52Mn]Mn-DOTA-JR11 exhibited a lower tumor uptake of 2.11 ± 0.30% ID/g 4 h post-injection. The synthesis of both radiotracers was accomplished with high RCY and purity. The cell uptake and internalization of [52Mn]Mn-DOTATATE showed higher levels compared to [52Mn]Mn-DOTA-JR11. PET images of the radiotracers in AR42J tumor bearing mice demonstrated similar biodistribution in all organs except the tumor, with [52Mn]Mn-DOTATATE showing higher tumor uptake compared to [52Mn]Mn-DOTA-JR11. The variations in properties of these tracers could be used to guide further imaging and treatment studies.

Development of the Precision-designed Radiopharmaceuticals Depending on the Targeting Molecules

Development of the Precision-designed Radiopharmaceuticals Depending on the Targeting Molecules

Effect of Linker Entities on Pharmacokinetics of 111In-Labeled Prostate-Specific Membrane Antigen-Targeting Ligands with an Albumin Binder.

In the field of radiopharmaceutical development targeting cancer, an albumin binder (ALB) is commonly used to improve accumulation of radioligands in tumors because it has high binding affinity for albumin and extends the circulation time of radioligands. The further development of ALB-containing radioligands is also expected to regulate their pharmacokinetics. In this study, we newly designed and synthesized [111In]In-PNT-DA1 derivatives, prostate-specific membrane antigen (PSMA)-targeting radioligands including a functional linker (d-glutamic acid or 4-(aminomethyl)benzoic acid), and evaluated the relationships among the structure, albumin-binding affinity, and pharmacokinetics. These derivatives showed a different binding affinity for albumin by the introduction of a linker. Biodistribution studies revealed that the introduction of a linker affects the pharmacokinetics of each derivative. The biodistribution studies also suggested that moderate albumin-binding affinity enhances the tumor/kidney ratio of the derivative. SPECT imaging using [111In]In-PNT-DA3 with the highest tumor/kidney ratio among [111In]In-PNT-DA1 derivatives led to clear visualization of a PSMA-positive LNCaP tumor. The results suggest that the appropriate introduction of linker entities may be necessary to improve the pharmacokinetics of PSMA-targeting radioligands.

Peptide derived from plant defensins: A promising 68Ga radiolabelled agent for diagnostic of infection foci in PET.

The development of new radiopharmaceuticals for the detection of hidden infection foci has great relevance for early detection and the selection of the correct treatment, particularly in immunosuppressed patients. In that sense, the labelling of antimicrobial peptides (AMPs) that are capable of binding specifically to the pathogenic microorganism which causes the infection, should provide a sufficiently specific agent, able to distinguish an infection from a sterile inflammation. Defensins are particularly interesting molecules with antimicrobial activity, the EcgDf1 defensin was identified from the genome of a Uruguayan native plant, Erythrina crista-galli, the 'Ceibo' tree. Our group has previously reported a synthetic biologically active short analogue EcgDf21 (ERFTGGHCRGFRRRCFCTKHC) successfully labelled with 99mTc. Herein we present a shorter analogue which also preserves the γ-core domain, as a pharmacophore for a potential infection detection agent. This peptide was derivatized with the bifunctional chelating agent 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) through a lysine linker in the amino-terminal group (NOTA-KGHCRGFRRRC) and radiolabelled with 68Ga ([68Ga]Ga-NOTA-K-EcgDf1(10)). The [68Ga]Ga-NOTA-K-EcgDf1(10) labelling procedure rendered a product with high radiochemical purity and stability in the labelling milieu. The Log P value indicated that the complex has a hydrophilic behaviour, confirmed by the biodistribution profile. The [68Ga]Ga-NOTA-K-EcgDf1(10) complex demonstrated specific binding to cultures of Candida albicans and Aspergillus niger. Its biodistribution showed renal elimination and low accumulation in the rest of the body. It was possible to successfully differentiate sterile inflammation from infection by PET images in nude mice with a target/non-target ratio of 3.3 for C. albicans and 3.7 for A. niger, respectively.

64Cu2+ Complexes of Tripodal Amine Ligands' In Vivo Tumor and Liver Uptakes and Intracellular Cu Distribution in the Extrahepatic Bile Duct Carcinoma Cell Line TFK-1: A Basic Comparative Study.

Copper (Cu) is a critical element for cancer cell proliferation and considerably accumulates in the nucleus. 64Cu2+ is an anticancer radiopharmaceutical that targets the copper requirement of cancer cells. However, intravenously injected 64Cu2+ ions primarily accumulate in the liver. Ligand complexation of 64Cu2+ may be a promising method for increasing tumor delivery by reducing liver uptake. In this study, we used three tripodal amine ligands [tris(2-aminoethyl)amine (Tren), diethylenetriamine (Dien), and tris(2-pyridylmethyl)amine (TPMA)] to enclose 64Cu2+ ions and compared their in vivo tumor and liver uptakes using a tumor-bearing xenograft mouse model of the extrahepatic bile duct carcinoma cell line TFK-1. We examined intracellular Cu distribution using microparticle-induced X-ray emission (micro-PIXE) analysis of these compounds. 64Cu2+-Tren and 64Cu2+-Dien showed higher tumor uptake than 64Cu2+-TPMA and 64Cu2+ ions in TFK-1 tumors. Among the three 64Cu2+ complexes and 64Cu2+ ions, liver uptake was inversely correlated with tumor uptake. Micro-PIXE analysis showed that in vitro cellular uptake was similar to in vivo tumor uptake, and nuclear delivery was the highest for 64Cu2+-Tren. Conclusively, an inverse correlation between tumor and liver uptake was observed using three 64Cu2+ complexes of tripodal amine ligands and 64Cu2+ ions. These results provide useful information for the future development of anticancer 64Cu radiopharmaceuticals.

PET Molecular Imaging in Breast Cancer: Current Applications and Future Perspectives.

Positron emission tomography (PET) plays a crucial role in breast cancer management. This review addresses the role of PET imaging in breast cancer care. We focus primarily on the utility of 18F-fluorodeoxyglucose (FDG) PET in staging, recurrence detection, and treatment response evaluation. Furthermore, we delve into the growing interest in precision therapy and the development of novel radiopharmaceuticals targeting tumor biology. This includes discussing the potential of PET/MRI and artificial intelligence in breast cancer imaging, offering insights into improved diagnostic accuracy and personalized treatment approaches.

Relevance of Oxocyclam from Palladium(II) Coordination to Radiopharmaceutical Development.

We provide a comprehensive study of the coordination of oxocyclam with palladium(II), including presentation of a novel bifunctional analogue, p-H2N-Bn-oxocyclam, bearing an aniline pendant. The complexation of palladium(II) with oxocyclam was examined by various techniques, including NMR analysis and potentiometric titrations which revealed that the Pd(II) complex can adopt different configurations such as trans-I and trans-III. In addition, oxocyclam forms a thermodynamically stable palladium(II) complex, the stabilization being attributed to the deprotonation of the amide function. The crystal structures of [Pd(H-1oxocyclam)]+ and [Pd(oxocyclam)]2+ were obtained, revealing the structural details previously anticipated, including, in the second case, the presence of the proton on the carbonyl oxygen atom. Additionally, the study explored the redox behavior of the Pd(II)-oxocyclam complex through reduction and oxidation voltammograms at different pH values. Successful 109Pd-labeling of oxocyclam and p-H2N-Bn-oxocyclam at pH 3.5 demonstrated high labeling efficiencies, whatever the species formed. The stability of the radiocomplexes was assessed and moderate transchelation toward EDTA was observed. Overall, oxocyclam displayed favorable properties for Pd(II) coordination and radiolabeling, suggesting its potential as a chelating agent for this metal in palladium-based applications.