Relating β+ radionuclides’ properties by order theory

We studied 27 β⁺ radionuclides taking into account some of their variants encoding information of their production, such as integral yield, threshold energy and energy of projectiles used to generate them; these radionuclides are of current use in clinical diagnostic imaging by positron emission tomography (PET). The study was conducted based on physical, physico-chemical, nuclear, dosimetric and quantum properties, which characterise the β⁺ radionuclides selected, with the aim of finding meaningful relationships among them. In order to accomplish this objective the mathematical methodology known as formal concept analysis was employed. We obtained a set of logical assertions (rules) classified as implications and associations, for the set of β⁺ radionuclides considered. Some of them show that low mass defect is related to high and medium values of maximum β⁺ energy, and with even parity and low mean lives; all these parameters are associated to the dose received by a patient subjected to a PET analysis.     

Radiochemistry,Production Processes,Labeling Methods,and ImmunoPET Imaging Pharmaceuticals of Iodine-124

Target-specific biomolecules, monoclonal antibodies (mAb), proteins, and protein fragments are known to have high specificity and affinity for receptors associated with tumors and other pathological conditions. However, the large biomolecules have relatively intermediate to long circulation half-lives (>day) and tumor localization times. Combining superior target specificity of mAbs and high sensitivity and resolution of the PET (Positron Emission Tomography) imaging technique has created a paradigm-shifting imaging modality, ImmunoPET. In addition to metallic PET radionuclides, ¹²⁴I is an attractive radionuclide for radiolabeling of mAbs as potential immunoPET imaging pharmaceuticals due to its physical properties (decay characteristics and half-life), easy and routine production by cyclotrons, and well-established methodologies for radioiodination. The objective of this report is to provide a comprehensive review of the physical properties of iodine and iodine radionuclides, production processes of ¹²⁴I, various ¹²⁴I-labeling methodologies for large biomolecules, mAbs, and the development of ¹²⁴I-labeled immunoPET imaging pharmaceuticals for various cancer targets in preclinical and clinical environments. A summary of several production processes, including ¹²³Te(d,n)¹²⁴I, ¹²⁴Te(d,2n)¹²⁴I, ¹²¹Sb(α,n)¹²⁴I, ¹²³Sb(α,3n)¹²⁴I, ¹²³Sb(³He,2n)¹²⁴I, ^natSb(α, xn)¹²⁴I, ^natSb(³He,n)¹²⁴I reactions, a detailed overview of the ¹²⁴Te(p,n)¹²⁴I reaction (including target selection, preparation, processing, and recovery of ¹²⁴I), and a fully automated process that can be scaled up for GMP (Good Manufacturing Practices) production of large quantities of ¹²⁴I is provided. Direct, using inorganic and organic oxidizing agents and enzyme catalysis, and indirect, using prosthetic groups, ¹²⁴I-labeling techniques have been discussed. Significant research has been conducted, in more than the last two decades, in the development of ¹²⁴I-labeled immunoPET imaging pharmaceuticals for target-specific cancer detection. Details of preclinical and clinical evaluations of the potential ¹²⁴I-labeled immunoPET imaging pharmaceuticals are described here.     

Fluorine-18 and medical imaging: Radiopharmaceuticals for positron emission tomography

Fluorine presents among its radioactive isotopes fluorine-18, that decays with a 109 min half-life and a β⁺ emission, allowing external detection of the two coincident γ photons obtained after annihilation. Production techniques (medical cyclotron), radiochemical reactions for isotope incorporation in radiopharmaceuticals and development of specific detection cameras (positron emission tomographs) allowed development of a vast investigation field in medical imaging.Applications of PET in oncology ([¹⁸F]fluorodeoxyglucose, FDG) largely improved detection and management of cancers; tracer molecules labelled with fluorine-18 also allow fruitful researches in molecular imaging.     

Kit-like <Superscript>18</Superscript>F-labeling of an estradiol derivative as a potential PET imaging agent for estrogen receptor-positive breast cancer

16α-¹⁸F-fluoroestradiol (¹⁸F-FES) has been developed as a promising positron emission tomography (PET) imaging agent for targeting estrogen receptor positive (ER⁺) breast cancer in the clinical trial. However, the radiosynthesis of ¹⁸F-FES often requires two steps and tough experimental conditions. Therefore, a new estradiol derivative (¹⁸F-AmBF₃-ES) was prepared by an efficient one-step ¹⁸F-radiolabeling method. The tracer was obtained in high yield (~65%) and excellent radiochemical purity (>98%) within 30 min. The uptake rate of ¹⁸F-AmBF₃-ES in ER⁺ cells was about 3.5% at 30 min. The results suggested that the tracer may be a potential PET imaging agent for ER⁺ breast cancer.     

Biomedical radioisotope generator systems

Although the⁹⁹Mo^99mTc radionuclide generator system has evolved as the workhorse of nuclear medicine over the past three decades, recent developments in radionuclide generator technology have provided positron emitters for PET studies, radionuclides for therapy, and ultra short-lived radionuclides for repeated clinical applications. Attention is being paid to development ofin vivo generator systems and potential use of tandem generator systems. Separation of radionuclides in a generator system exploits differences in chemical properties of the parent-daughter pair; information is presented for these generator types based on the three chemical categories of chromatography, extraction, and volatilization and sublimation methods. This review focuses on chromatography-based systems.     

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

Positron emission tomography (PET) is a molecular imaging technology that provides quantitative information about function and metabolism in biological processes in vivo for disease diagnosis and therapy assessment. The broad application and rapid advances of PET has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron‐emitting radionuclides. This Review provides an overview of commonly used labeling reactions through examples of clinically relevant PET tracers and highlights the most recent developments and breakthroughs over the past decade, with a focus on ¹¹C, ¹⁸F, ¹³N, and ¹⁵O.     

Synthesis and Evaluation of [18F]‐Ammonium BODIPY Dyes as Potential Positron Emission Tomography Agents for Myocardial Perfusion Imaging

Recently, we demonstrated the potential of a [¹⁸F]‐trimethylammonium BODIPY dye for cardiac imaging. This is the first example of the use of the [¹⁸F]‐ammonium BODIPY dye for positron emission tomography (PET) myocardial perfusion imaging (MPI). In this report, we extend our study to other ammonium BODIPY dyes with different nitrogen substituents. These novel ammonium BODIPY dyes were successfully prepared and radiolabeled by the SnCl₄‐assisted ¹⁸F–¹⁹F isotopic exchange method. The microPET results and the biodistribution data reveal that nitrogen substituent changes have a significant effect on the in vivo and pharmacological properties of the tracers. Of the novel [¹⁸F]‐ammonium BODIPY dyes prepared in this work, the [¹⁸F]‐dimethylethylammonium BODIPY is superior in terms of myocardium uptake and PET imaging contrast. These results support our hypothesis that the ammonium BODIPY dyes have a great potential for use as PET/optical dual‐modality MPI probes.     

Establishing Radiolanthanum Chemistry for Targeted Nuclear Medicine Applications

We report the first targeted nuclear medicine application of the lanthanum radionuclides ^132/135La. These isotopes represent a matched pair for diagnosis via the positron emissions of ¹³²La and therapy mediated by the Auger electron emissions of ¹³⁵La. We identify two effective chelators, known as DO3Apic and macropa, for these radionuclides. The 18-membered macrocycle, macropa, bound ^132/135La with better molar activity than DO3Apic under similar conditions. These chelators were conjugated to the prostate-specific membrane antigen (PSMA)-targeting agent DUPA to assess the use of radiolanthanum for in vivo imaging. The ^132/135La-labeled targeted constructs showed high uptake in tumor xenografts expressing PSMA. This study validates the use of these radioactive lanthanum isotopes for imaging applications and motivates future work to assess the therapeutic effects of the Auger electron emissions of ¹³⁵La.     

PET Diagnostic Molecules Utilizing Multimeric Cyclic RGD Peptide Analogs for Imaging Integrin αvβ3 Receptors

Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin α_vβ₃ receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin α_vβ₃ receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin α_vβ₃ tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (¹⁸F, ⁶⁴Cu, and ⁶⁸Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included.     

Enzyme mediated incorporation of zirconium-89 or copper-64 into a fragment antibody for same day imaging of epidermal growth factor receptor

Identification of tumors which over-express Epidermal Growth Factor Receptor (EGFR) is important in selecting patients for anti-EGFR therapies. Enzymatic bioconjugation was used to introduce positron-emitting radionuclides (⁸⁹Zr, ⁶⁴Cu) into an anti-EGFR antibody fragment for Positron Emission Tomography (PET) imaging the same day as injection. A monovalent antibody fragment with high affinity for EGFR was engineered to include a sequence that is recognized by the transpeptidase sortase A. Two different metal chelators, one for ⁸⁹Zr^IV and one for ⁶⁴Cu^II, were modified with a N-terminal glycine to enable them to act as substrates in sortase A mediated bioconjugation to the antibody fragment. Both fragments provided high-quality PET images of EGFR positive tumors in a mouse model at 3 hours post-injection, a significant advantage when compared to radiolabeled full antibodies that require several days between injection of the tracer and imaging. The use of enzymatic bioconjugation gives reproducible homogeneous products with the metal complexes selectively installed on the C-terminus of the antibody potentially simplifying regulatory approval.

Enzymatic bioconjugation to introduce positron-emitting radionuclides (⁸⁹Zr, ⁶⁴Cu) into an anti-EGFR antibody fragment allows same day imaging with positron emission tomography.     

Production of no-carrier-added 64Cu and applications to molecular imaging by PET and PETIS as a biomedical tracer

Copper-64 was produced by the ⁶⁴Ni(p, n)⁶⁴Cu reaction using enriched ⁶⁴NiO target. We investigated and compared the production yield of ⁶⁴Cu for proton beams of various energies by using a thick target. Enriched ⁶⁴Ni was recovered with high yield by simple procedures. Imaging studies using positron emission tomography (PET) and positron emitting tracer imaging system (PETIS) were performed. We obtained clear images in PET and PETIS studies. The results of this study indicate that ⁶⁴Cu can be utilized as a biomedical tracer for the molecular imaging both in animals and plants.     

Studies on sorption of antimony and europium from liquid organic and aqueous radioactive wastes on different sorbents

Sorption of¹²⁴Sb(III) from benzene, toluene, o-xylene and nitrobenzene on treated fly ash, pyrolysis residue and bentonite clay was studied at room temperature using the batch method. In comparison to a former study for the sorption of¹²⁴Sb(V), the results revealed relatively higher sorption of the trivalent state than the pentavalent one. According to the type of the nonpolar solvent used, the order of uptake of the radioactive isotopes was often o-xylenetoluene>benzene. The sorption tendency of the sorbents used towards the radionuclides was: bentonitepyrolysis residue>treated fly ash. Sorption from an aqueous medium on the same sorbents has also been investigated for¹²⁴Sb(III) compared to¹²⁴Sb(V),¹⁵²Eu(III) and their mixtures. The obtained results showed that the order of uptake of the different radionuclides was: Eu(III)>>Sb(III)>Sb(V)>mixture. The investigation was extended to the desorption studies of these radionuclides in the acidic and the neutral media from the dried radioactivity loaded sorbents.     

Syntheses of o-iodobenzyl alcohols‒BODIPY structures as potential precursors of bimodal tags for positron emission tomography and optical imaging

Aiming the faster development from bench to bedside of new potential tracers, multimodal tracers for positron emission tomography (PET) and optical imaging (OI) have emerged as a very promising tool. Indeed, they combine the simplicity of use of optical techniques for in vitro/in vivo pre-clinical studies with the various clinical possibilities offered by PET imaging using their radioactive versions. In this context, the preparation of new tags detectable by fluorescence imaging and potentially suitable for PET imaging after a last-step ¹¹C-labeling of the corresponding precursor has been investigated. Various designs and syntheses were explored by linking o-iodobenzyl alcohols and tetramethyl-BODIPY moieties together. Among them, the most promising structure was produced in 30% yield over five steps from a commercially available and inexpensive starting material.     

Site‐Selective,Late‐Stage C−H 18F‐Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging

Peptides are often ideal ligands for diagnostic molecular imaging due to their ease of synthesis and tuneable targeting properties. However, labelling unmodified peptides with ¹⁸F for positron emission tomography (PET) imaging presents a number of challenges. Here we show the combination of photoactivated sodium decatungstate and [¹⁸F]‐N‐fluorobenzenesulfonimide effects site‐selective ¹⁸F‐fluorination at the branched position in leucine residues in unprotected and unaltered peptides. This streamlined process provides a means to directly convert native peptides into PET imaging agents under mild aqueous conditions, enabling rapid discovery and development of peptide‐based molecular imaging tools.     

Site‐Selective,Late‐Stage C−H 18F‐Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging

Peptides are often ideal ligands for diagnostic molecular imaging due to their ease of synthesis and tuneable targeting properties. However, labelling unmodified peptides with ¹⁸F for positron emission tomography (PET) imaging presents a number of challenges. Here we show the combination of photoactivated sodium decatungstate and [¹⁸F]‐N‐fluorobenzenesulfonimide effects site‐selective ¹⁸F‐fluorination at the branched position in leucine residues in unprotected and unaltered peptides. This streamlined process provides a means to directly convert native peptides into PET imaging agents under mild aqueous conditions, enabling rapid discovery and development of peptide‐based molecular imaging tools.     

Copper‐64‐Alloyed Gold Nanoparticles for Cancer Imaging: Improved Radiolabel Stability and Diagnostic Accuracy

Gold nanoparticles, especially positron‐emitter‐ labeled gold nanostructures, have gained steadily increasing attention in biomedical applications. Of the radionuclides used for nanoparticle positron emission tomography imaging, radiometals such as ⁶⁴Cu have been widely employed. Currently, radiolabeling through macrocyclic chelators is the most commonly used strategy. However, the radiolabel stability may be a limiting factor for further translational research. We report the integration of ⁶⁴Cu into the structures of gold nanoparticles. With this approach, the specific radioactivity of the alloyed gold nanoparticles could be freely and precisely controlled by the addition of the precursor ⁶⁴CuCl₂ to afford sensitive detection. The direct incorporation of ⁶⁴Cu into the lattice of the gold nanoparticle structure ensured the radiolabel stability for accurate localization in vivo. The superior pharmacokinetic and positron emission tomography imaging capabilities demonstrate high passive tumor targeting and contrast ratios in a mouse breast cancer model, as well as the great potential of this unique alloyed nanostructure for preclinical and translational imaging.     

Tuning Tetrazole Photochemistry for Protein Ligation and Molecular Imaging

Photochemistry provides a wide range of alternative reagents that hold potential for use in bimolecular functionalisation of proteins. Here, we report the synthesis and characterisation of metal ion binding chelates derivatised with disubstituted tetrazoles for the photoradiochemical labelling of monoclonal antibodies (mAbs). The photophysical properties of tetrazoles featuring extended aromatic systems and auxochromic substituents to tune excitation toward longer wavelengths (365 and 395 nm) were studied. Two photoactivatable chelates based on desferrioxamine B (DFO) and the aza-macrocycle NODAGA were functionalised with a tetrazole and developed for protein labelling with ⁸⁹Zr, ⁶⁴Cu and ⁶⁸Ga radionuclides. DFO-tetrazole ( 1 ) was assessed by direct conjugation to formulated trastuzumab and subsequent radiolabelling with ⁸⁹Zr. Radiochemical studies and cellular-based binding assays demonstrated that the radiotracer remained stable in vitro retained high immunoreactivity. Positron emission tomography (PET) imaging and biodistribution studies were used to measure the tumour specific uptake and pharmacokinetic profile in mice bearing SK-OV-3 xenografts. Experiments demonstrate that tetrazole-based photochemistry is a viable approach for the light-induced synthesis of PET radiotracers.     

64Cu radiolabeled nanomaterials for positron emission tomography (PET) imaging

The prevalence of positron emission tomography (PET) imaging has advanced biomedical applications for its ultrahigh sensitivity, deep tissue penetration and quantitative visualization of diseases in vivo. ⁶⁴Cu with ideal half-life and decay characteristics has been designed as radioactive probes for disease diagnosis. The currently reported ⁶⁴Cu-labeled nanomaterials have the advantages of long circulation time in serum, good biocompatibility and mature preparation methods, and have been used in vivo PET imaging, biodistribution and pharmacokinetic monitoring, and imaging guided therapy. At the same time, suitable carrier characteristics and radiolabeling strategies are particularly important in the ⁶⁴Cu PET imaging process. In this review, we summarize different imaging probe designs and ⁶⁴Cu radiolabeling strategies, as well as their eventual applications in biomedicine. The potential challenges and prospects of ⁶⁴Cu labeled nanomaterials are also described, which provides broad prospects for radiolabeling strategies and further applications.     

On the use of5 5Co in nuclear medicine —Its disadvantage and possible substitute

The use of^{5 5}Co for positron emission tomography (PET) is criticized on the grounds that its 477 keV -rays would interfere with the positron annihilation measurements. This interference will lead to distorded pictures, lower resolution and lower tumor-non tumor ratios for^{5 5}Co-bleomycin. It is suggested that^{5 7}Co-bleomycin used in single photon imaging is better replaced by^{5 7}Ni-bleomycin rather than by^{5 5}Co-bleomycin for PET studies.     

New developments in the production of theranostic pairs of radionuclides

A brief historical background of the development of the theranostic approach in nuclear medicine is given and seven theranostic pairs of radionuclides, namely ^44gSc/⁴⁷Sc, ⁶⁴Cu/⁶⁷Cu, ⁸³Sr/⁸⁹Sr, ⁸⁶Y/⁹⁰Y, ¹²⁴I/¹³¹I, ¹⁵²Tb/¹⁶¹Tb and ¹⁵²Tb/¹⁴⁹Tb, are considered. The first six pairs consist of a positron and a β^?-emitter whereas the seventh pair consists of a positron and an α-particle emitter. The decay properties of all those radionuclides are briefly mentioned and their production methodologies are discussed. The positron emitters ⁶⁴Cu, ⁸⁶Y and ¹²⁴I are commonly produced in sufficient quantities via the (p,n) reaction on the respective highly enriched target isotope. A clinical scale production of the positron emitter ^44gSc has been achieved via the generator route as well as via the (p,n) reaction, but further development work is necessary. The positron emitters ⁸³Sr and ¹⁵²Tb are under development. Among the therapeutic radionuclides, ⁸⁹Sr, ⁹⁰Y and ¹³¹I are commercially available and ¹⁶¹Tb can also be produced in sufficient quantity at a nuclear reactor. Great efforts are presently underway to produce ⁴⁷Sc and ⁶⁷Cu via neutron, photon and charged particle induced reactions. The radionuclide ¹⁴⁹Tb is unique because it is an α-particle emitter. The present method of production of ¹⁵²Tb and ¹⁴⁹Tb involves the use of the spallation process in combination with an on-line mass separator. The role of some emerging irradiation facilities in the production of special radionuclides is discussed.