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This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like 211At, 223Ra, 225Ac/213Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

Plant secondary metabolites have been a fertile area of chemical investigation for many years, driving the development of both analytical chemistry and of new synthetic reactions and methodologies. The subject is multi-disciplinary with chemists, biochemists and plant scientists all contributing to our current understanding. In recent years there has been an upsurge in interest from other disciplines, related to the realisation that secondary metabolites are dietary components that may have a considerable impact on human health, and to the development of gene technology that permits modulation of the contents of desirable and undesirable components. Plant Secondary Metabolites: Occurrence, Structure and Role in the Human Diet addresses this wider interest by covering the main groups of natural products from a chemical and biosynthetic perspective with illustrations of how genetic engineering can be applied to manipulate levels of secondary metabolites of economic value as well as those of potential importance in diet and health. These descriptive chapters are augmented by chapters showing where these products are found in the diet, how they are metabolised and reviewing the evidence for their beneficial bioactivity.

Purpose The unsatisfactory efficacy of PD-L1 antibodies in glioblastoma (GBM) is largely due to the temporal and spatial heterogeneity of PD-L1 expression. Molecular imaging can enhance understanding of the tumor immune microenvironment and guide immunotherapy. However, highly sensitive imaging agents capable of effectively visualizing PD-L1 heterogeneity are limited. This study introduces a novel PET tracer, offering improved imaging of PD-L1 heterogeneity in GBM xenografts, with a comparative analysis to [ 18 F]AlF-NOTA-WL12. Methods [ 18 F]AlF-NOTA-PCP2 was synthesized with high purity and its affinity for PD-L1 was characterized using surface plasmon resonance (SPR) and cell binding assays. Its specificity for PD-L1 was evaluated both in vitro using various cell lines and in vivo with GBM xenograft models in NOD/SCID mice. PET/CT imaging was conducted to evaluate the tracer’s biodistribution, pharmacokinetics, and ability to quantify tumoral spatial heterogeneity of PD-L1 expression. A focused comparative analysis between [ 18 F]AlF-NOTA-PCP2 and [ 18 F]AlF-NOTA-WL12 was conducted, examining binding affinity, biodistribution, pharmacokinetics, and imaging effectiveness in GBM xenografts. Additionally, human radiation dosimetry estimates compared the safety profiles of both tracers. Results [ 18 F]AlF-NOTA-PCP2 demonstrated high radiochemical purity (> 95%) and a strong affinity for PD-L1, comparable to [ 18 F]AlF-NOTA-WL12. In vitro and in vivo studies confirmed its specificity for PD-L1, with increased uptake in PD-L1 expressing cells and tumors. Toxicological profiles indicated no significant abnormalities in serum biochemical indicators or major organ tissues. MicroPET/CT imaging showed [ 18 F]AlF-NOTA-PCP2’s effectiveness in visualizing PD-L1 expression levels and spatial heterogeneity in GBM xenografts. Comparative studies revealed [ 18 F]AlF-NOTA-PCP2’s improved pharmacokinetic properties, including higher tumor-to-blood ratios and lower nonspecific liver uptake, as well as reduced radiation exposure compared to [ 18 F]AlF-NOTA-WL12. Conclusion [ 18 F]AlF-NOTA-PCP2 distinguishes itself as an exceptionally sensitive PET/CT tracer, adept at non-invasively and accurately quantifying PD-L1 expression and its spatial heterogeneity in tumors, especially in GBM. Its favorable pharmacokinetic properties, safety profile, and high affinity for PD-L1 highlight its potential for enhancing the precision of cancer immunotherapy and guiding individualized treatment strategies. While promising, its clinical translation, especially in brain imaging, necessitates further validation in clinical trials.

Purpose Trophoblast glycoprotein, the so-called 5T4, is an oncofetal antigen expressed in many different cancers. However, no 5T4-specific radioligand is employed in the clinic for non-invasive diagnosis. Thus, the aim of the current study was to develop a PET radiotracer for imaging 5T4 expression in preclinical and clinical stages. Methods A VHH library was constructed by camel immunization. The specificity of the VHHs toward 5T4 antigen was screened through phage display biopanning and periplasmic extract enzyme-linked immunosorbent assay. 1,4,7-Triazacyclononane-1,4,7-triacetate acid (NOTA) derivative was conjugated to the selected VHH. After radiolabeling, microPET/CT and ex vivo biodistribution were conducted using BxPC-3 and MDA-MB-468 tumor-bearing mice. Cold VHH was co-injected with the tracer to challenge its binding in vivo. For the pilot clinical study, PET/CT images were acquired at 1 h after injection of tracer in patients with pathologically confirmed primary and metastatic tumors. Results A library with a capacity of 1.2 × 10 12 colony-forming units was constructed after successful camel immunization. Nb1-40 with a median effect concentration of 0.43 nM was selected. After humanization, the resulting H006 maintained a high affinity towards 5T4. [ 68 Ga]Ga-NOTA-H006 with the molar activities of 6.48–54.2 GBq/µmol was prepared with high radiochemical purity (> 98%). Using [ 68 Ga]Ga-NOTA-H006, microPET/CT revealed a clear visualization of 5T4 expression in BxPC-3 tumor-bearing mice. Ex vivo biodistribution showed that the highest tumor-to-blood ratio (∼ 3-fold) and tumor-to-muscle ratio (∼ 5-fold) were achieved at 60 min post-injection. Co-injection of the cold H006 at a dose of 1.5 mg/kg significantly reduced the tumor uptake ( p  < 0.0001). In the pilot clinical study, [ 68 Ga]Ga-NOTA-H006 demonstrated its capacity to map 5T4-positive lesions in humans and yielded a mean effective dose of 3.4 × 10 − 2 mSv/MBq. Conclusions [ 68 Ga]Ga-NOTA-H006, which can visualize 5T4 expression in vivo, has been successfully developed. This opens up opportunities for non-invasively studying 5T4 expression through nuclear medicine. Further clinical investigations are warranted to explore its clinical value in disease progression and companion diagnosis.

Purpose Vascular endothelial growth factor receptor 3 (VEGFR-3) plays a critical role in tumor lymphangiogenesis and metastasis, holding promise as a promising therapeutic target for solid tumors. TMVP1 (LARGR) is a 5-amino acid peptide previously identified in our laboratory from bacterial peptide display system that specifically targets VEGFR-3. Radiolabeled TMVP1 can be used for non-invasive imaging of VEGFR-3 expressing tumors. Homodimeric peptides have better targeting ability than monomeric peptides, and it is worth exploring whether homodimers of TMVP1 ((TMVP1) 2 ) can achieve better imaging effects. This study aimed to explore the peptide properties and tumor assessment value of [ 68 Ga]Ga-labeled (TMVP1) 2 . Methods In this study, we developed a TMVP1 homodimer that was conjugated with 1,4,7-triazacyclononane-N, N′, N″-triacetic acid (NOTA) via tetraethyleneglycol (PEG 4 ) and triglyicine (Gly 3 ) spacer, and labeled with 68 Ga, to construct [ 68 Ga]Ga-NOTA-(TMVP1) 2 . Binding of VEGFR-3 by TMVP1 and (TMVP1) 2 , respectively, was modeled by molecular docking. The affinity of [ 68 Ga]Ga-NOTA-(TMVP1) 2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [ 68 Ga]Ga-NOTA-(TMVP1) 2 were performed in subcutaneous C33A cervical cancer xenografts. Five healthy volunteers and eight patients with cervical cancer underwent whole-body PET/CT acquisition 30–45 min after intravenous injection of [ 68 Ga]Ga-NOTA-(TMVP1) 2 . Results Both molecular docking and cellular experiments showed that homodimeric TMVP1 had a higher affinity for VEGFR-3 than monomeric TMVP1. [ 68 Ga]Ga-NOTA-(TMVP1) 2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [ 68 Ga]Ga-NOTA-(TMVP1) 2 specifically localized in the tumor (2.32 ± 0.10% ID/g). Pretreatment of C33A xenograft mice with the unlabeled peptide NOTA-(TMVP1) 2 reduced the enrichment of [ 68 Ga]Ga-NOTA-(TMVP1) 2 in tumors (0.58 ± 0.01% ID/g). [ 68 Ga]Ga-NOTA-(TMVP1) 2 proved to be safe in all healthy volunteers and recruited patients, with no side effects or allergies noted. In cervical cancer patients, a majority of the [ 18 F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [ 68 Ga]Ga-NOTA-(TMVP1) 2. SUVmax and SUVmean were 2.32 ± 0.77 and 1.61 ± 0.48, respectively. With normal muscle (gluteus maximus) as background, tumor-to-background ratios were 3.49 ± 1.32 and 3.95 ± 1.64 based on SUVmax and SUVmean, respectively. Conclusion The favorable characterizations of [ 68 Ga]Ga-NOTA-(TMVP1) 2 such as convenient synthesis, high specific activity, and high tumor uptake enable the evaluation of VEGFR-3 in cervical cancer patients and warrant further clinical studies. Trial registration ChiCTR-DOD-17012458. Registered August 23, 2017 (retrospectively registered).

Genetic code expansion (GCE) technology allows the specific incorporation of functionalized noncanonical amino acids (ncAAs) into proteins. Here, we investigated the Diels-Alder reaction between trans-cyclooct-2-ene (TCO)-modified ncAAs, and 22 known and novel 1,2,4,5-tetrazine-dye conjugates spanning the entire visible wavelength range. A hallmark of this reaction is its fluorogenicity - the tetrazine moiety can elicit substantial quenching of the dye. We discovered that photoinduced electron transfer (PET) from the excited dye to tetrazine is the main quenching mechanism in red-absorbing oxazine and rhodamine derivatives. Upon reaction with dienophiles quenching interactions are reduced resulting in a considerable increase in fluorescence intensity. Efficient and specific labeling of all tetrazine-dyes investigated permits super-resolution microscopy with high signal-to-noise ratio even at the single-molecule level. The different cell permeability of tetrazine-dyes can be used advantageously for specific intra- and extracellular labeling of proteins and highly sensitive fluorescence imaging experiments in fixed and living cells. Gerti Beliu et al. characterise the properties of tetrazine dyes, labelling proteins through site-specific introduction of a non-canonical amino acids followed by bioorthogonal click chemistry and evaluate the usefulness of tetrazine dyes for super-resolution microscopy.

Background Primary aldosteronism (PA) is a leading cause of secondary hypertension, but the lack of representative preclinical models hampers translational research and imaging evaluation. We aimed to establish a patient-derived organoids-based xenograft (PDOX) model of PA and to assess its imaging characteristics using [ 18 F]AlF-NOTA-pentixather PET/CT, with validation in clinical patients. Methods Adrenal tissues from patients with PA were used to generate adrenal organoids in vitro. After serial passaging, these organoids were implanted subcutaneously into immunodeficient mice to establish PA PDOX models. The xenografted mice were subjected to [ 18 F]AlF-NOTA-pentixather PET/CT to evaluate tracer uptake and lesion detectability. In parallel, clinical PA patients underwent [ 18 F]AlF-NOTA-pentixather PET/CT to assess the imaging performance in a clinical setting. Results The PDOX models successfully engrafted and proliferated in vivo, maintaining key pathological features of PA. [ 18 F]AlF-NOTA-pentixather PET/CT imaging in the PDOX models demonstrated high and specific tracer uptake in xenografted lesions, with strong concordance to histopathological findings. In clinical PA patients, [ 18 F]AlF-NOTA-pentixather PET/CT also showed excellent performance in localizing PA lesions and provided valuable diagnostic information. Conclusion We established a novel PDOX model of PA and demonstrated the effectiveness of [ 18 F]AlF-NOTA-pentixather PET/CT in both preclinical and clinical applications. This approach provides a robust translational platform for mechanistic studies and for advancing precision imaging and therapy in PA.

Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo–electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.

Heterocyclic compounds play a vital role in the metabolism of living cells. Their practical applications range from extensive clinical use to fields as diverse as agriculture, photography, biocide formulation and polymer science. Written by leading scholars and industry experts, this book is thoroughly updated with over 50% new content. It has been rewritten with a new expanded author team, who have carefully distilled essential information on the reactivity, structure and synthesis of heterocycles from the 2008 major reference work Comprehensive Heterocyclic Chemistry III. To bring the work up to date the author team have also added new synthetic examples and structures, key applications and new references from 2008-2010.