PAMAM Dendrimer‐Based Nanodevices for Nuclear Medicine Applications

Nuclear medicine, involving nuclear medicine imaging and radiotherapy (RT), has become a mainstay of theranostics in the field of nanomedicine and several examples have been successfully translated into clinical practice. The combination of radionuclides with dendrimers has long been investigated in nuclear imaging, such as positron emission tomography (PET) and single‐photon emission computed tomography (SPECT), providing functional information for whole body quantitative analysis with high sensitivity due to the unique structural advantages of the dendrimer platform. Besides, radioisotopes with both therapeutic and imaging functionalities can also be combined with dendrimer platforms for theranostic applications. In this review, the recent advances in the development of radionuclide‐labeled poly(amidoamine) dendrimer‐based nanodevices for targeted PET, SPECT, SPECT/computed tomography, SPECT/magnetic resonance imaging of tumors, RT, as well as for SPECT‐imaging‐guided RT of cancer are summarized. Current restrictions hindering the clinical translation of dendrimer‐based nuclear nanodevices and future prospects are also discussed.     

Fluorine-18 Radiolabelling and Photophysical Characteristics of Multimodal PET–Fluorescence Molecular Probes

Positron emission tomography (PET)–fluorescence imaging is an emerging field of multimodality imaging seeking to attain synergy between the two techniques. The probes employed in PET–fluorescence imaging incorporate both a fluorophore and radioisotope which enable complementary information to be obtained from both imaging techniques via the administration of a single agent. Fluorine-18 is the most commonly used radioisotope in PET imaging and consequently many novel attempts to radiofluorinate various fluorophores have transpired over the past decade. In this Minireview, the most relevant fluorine-18 labelled PET–fluorescence probes have been classified into four groups as per the implemented fluorophore: 1) boron-dipyrromethene (BODIPY) dyes, 2) cyanine dyes, 3) alternative organic fluorophores and 4) organometallics, such as quantum dots (QDs) and rhenium complexes. The biological, radiochemical and photophysical properties of each probe have been systematically compared to aid future endeavours in PET–fluorescence chemistry.     

Bioimaging Based on Nucleic Acid Nanostructures

Nucleic acid nanostructures with structural programmability, spatial addressability and excellent biocompatibility have drawn much attention in various biomedical applications, such as bioimaging, biosensing and drug delivery. In this review, we summarize the recent research progress in the field of bioimaging based on nucleic acid nanostructures with different imaging models, including fluorescent imaging(FI), magnetic resonance imaging(MRI), photoacoustic imaging(PAI) and positron emission tomography/computed tomography(PET/CT) imaging. We also discuss the remaining challenges and further opportunities involved in the bioimaging research based on nucleic acid nanostructures.     

Efficient Uptake of 177Lu‐Porphyrin‐PEG Nanocomplexes by Tumor Mitochondria for Multimodal‐Imaging‐Guided Combination Therapy

The benefits to intracellular drug delivery from nanomedicine have been limited by biological barriers and to some extent by targeting capability. We investigated a size‐controlled, dual tumor‐mitochondria‐targeted theranostic nanoplatform (Porphyrin‐PEG Nanocomplexes, PPNs). The maximum tumor accumulation (15.6 %ID g^?1, 72 h p.i.) and ideal tumor‐to‐muscle ratio (16.6, 72 h p.i.) was achieved using an optimized PPN particle size of approximately 10 nm, as measured by using PET imaging tracing. The stable coordination of PPNs with ¹⁷⁷Lu enables the integration of fluorescence imaging (FL) and photodynamic therapy (PDT) with positron emission tomography (PET) imaging and internal radiotherapy (RT). Furthermore, the efficient tumor and mitochondrial uptake of ¹⁷⁷Lu‐PPNs greatly enhanced the efficacies of RT and/or PDT. This work developed a facile approach for the fabrication of tumor‐targeted multi‐modal nanotheranostic agents, which enables precision and radionuclide‐based combination tumor therapy.     

Applications of “Hot” and “Cold” Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging

The applications of coordination chemistry to molecular imaging has become a matter of intense research over the past 10 years. In particular, the applications of bis(thiosemicarbazonato) metal complexes in molecular imaging have mainly been focused on compounds with aliphatic backbones due to the in vivo imaging success of hypoxic tumors with PET (positron emission tomography) using ⁶⁴CuATSM [copper (diacetyl‐bis(N4‐methylthiosemicarbazone))]. This compound entered clinical trials in the US and the UK during the first decade of the 21^st century for imaging hypoxia in head and neck tumors. The replacement of the ligand backbone to aromatic groups, coupled with the exocyclic N's functionalization during the synthesis of bis(thiosemicarbazones) opens the possibility to use the corresponding metal complexes as multimodal imaging agents of use, both in vitro for optical detection, and in vivo when radiolabeled with several different metallic species. The greater kinetic stability of acenaphthenequinone bis(thiosemicarbazonato) metal complexes, with respect to that of the corresponding aliphatic ATSM complexes, allows the stabilization of a number of imaging probes, with special interest in “cold” and “hot” Cu(II) and Ga(III) derivatives for PET applications and ¹¹¹In(III) derivatives for SPECT (single‐photon emission computed tomography) applications, whilst Zn(II) derivatives display optical imaging properties in cells, with enhanced fluorescence emission and lifetime with respect to the free ligands. Preliminary studies have shown that gallium‐based acenaphthenequinone bis(thiosemicarbazonato) complexes are also hypoxia selective in vitro, thus increasing the interest in them as new generation imaging agents for in vitro and in vivo applications.     

DMAP‐BODIPY Alkynes: A Convenient Tool for Labeling Biomolecules for Bimodal PET–Optical Imaging

Several new boron dipyrromethene/N,N‐dimethylaminopyridine (BODIPY‐DMAP) assemblies were synthesized as precursors for bimodal imaging probes (optical imaging, OI/positron emission tomography, PET). The photophysical properties of the new compounds were also studied. The first proof‐of‐concept was obtained with the preparation of several new BODIPY‐labeled bombesins and evaluation of the affinity for bombesin receptors by using a competition binding assay. Fluorination reactions were investigated on DMAP‐BODIPY precursors as well as on DMAP‐BODIPY‐labeled bombesins. Chemical modifications on the BODIPY core were also performed to obtain luminescent dyes emitting in the therapeutic window (650–900 nm), suitable for in vivo imaging, making these compounds promising precursors for PET/optical dual‐modality imaging agents.     

Strained Cyclooctyne as a Molecular Platform for Construction of Multimodal Imaging Probes

Small‐molecule‐based multimodal and multifunctional imaging probes play prominent roles in biomedical research and have high clinical translation ability. A novel multimodal imaging platform using base‐catalyzed double addition of thiols to a strained internal alkyne such as bicyclo[6.1.0]nonyne has been established in this study, thus allowing highly selective assembly of various functional units in a protecting‐group‐free manner. Using this molecular platform, novel dual‐modality (PET and NIRF) uPAR‐targeted imaging probe: ⁶⁴Cu‐CHS1 was prepared and evaluated in U87MG cells and tumor‐bearing mice models. The excellent PET/NIRF imaging characteristics such as good tumor uptake (3.69 %ID/g at 2 h post‐injection), high tumor contrast, and specificity were achieved in the small‐animal models. These attractive imaging properties make ⁶⁴Cu‐CHS1 a promising probe for clinical use.     

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.     

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.     

Chelator‐Free Radiolabeling of Nanographene: Breaking the Stereotype of Chelation

Macrocyclic chelators have been widely employed in the realm of nanoparticle‐based positron emission tomography (PET) imaging, whereas its accuracy remains questionable. Here, we found that ⁶⁴Cu can be intrinsically labeled onto nanographene based on interactions between Cu and the π electrons of graphene without the need of chelator conjugation, providing a promising alternative radiolabeling approach that maintains the native in vivo pharmacokinetics of the nanoparticles. Due to abundant π bonds, reduced graphene oxide (RGO) exhibited significantly higher labeling efficiency in comparison with graphene oxide (GO) and exhibited excellent radiostability in vivo. More importantly, nonspecific attachment of 1,4,7‐triazacyclononane‐1,4,7‐triacetic acid (NOTA) on nanographene was observed, which revealed that chelator‐mediated nanoparticle‐based PET imaging has its inherent drawbacks and can possibly lead to erroneous imaging results in vivo.     

Fluorescent gallium and indium bis(thiosemicarbazonates) and their radiolabelled analogues: synthesis, structures and cellular confocal fluorescence imaging investigations

New fluorescent and biocompatible aromatic Ga(III)- and In(III)-bis(thiosemicarbazonato) complexes for dual mode optical and PET or SPECT molecular imaging have been synthesised via a synthetic method based on transmetallation reactions from Zn(II) precursors. Complexes have been fully characterised in the solid state by single crystal X-ray diffraction and in solution by spectroscopic methods (UV/Vis, fluorescence, (1)H and (13)C{(1)H} NMR). The bis(thiosemicarbazones) radiolabelled rapidly in high yields under mild conditions with (111)In (a gamma and Auger emitter for SPECT imaging and radiotherapy with t(1/2) = 2.8 d) and (68)Ga (a generator-available positron emitter for PET imaging with t(1/2) = 68 min). Cytotoxicity and biolocalisation studies using confocal fluorescence imaging and fluorescence lifetime imaging (FLIM) techniques have been used to study their in vitro activities and stabilities in HeLa and PC-3 cells to ascertain their suitability as synthetic scaffolds for future multimodality molecular imaging in cancer diagnosis and therapy. The observation that the indium complexes show certain nuclear uptake could be of relevance towards developing (111)In therapeutic agents based on Auger electron emission to induce DNA damage.     

A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer

Recently, prostate-specific membrane antigen (PSMA) has gained momentum in tumor nuclear molecular imaging as an excellent target for both the diagnosis and therapy of prostate cancer. Since 2008, after years of preclinical research efforts, a plentitude of radiolabeled compounds mainly based on low molecular weight PSMA inhibitors (PSMA-i) have been described for imaging and theranostic applications, and some of them have been transferred to the clinic. Most of these compounds include radiometals (e.g., ⁶⁸Ga, ⁶⁴Cu, ¹⁷⁷Lu) for positron emission tomography (PET) imaging or endoradiotherapy. Nowadays, although the development of new PET tracers has caused a significant drop in single-photon emission tomography (SPECT) research programs and the development of new technetium-99m (^99mTc) tracers is rare, this radionuclide remains the best atom for SPECT imaging owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry. Indeed, ^99mTc still plays a relevant role in diagnostic nuclear medicine, as the number of clinical examinations based on ^99mTc outscores that of PET agents and ^99mTc-PSMA SPECT/CT may be a cost-effective alternative for ⁶⁸Ga-PSMA PET/CT. This review aims to give an overview of the specific features of the developed [^99mTc]Tc-tagged PSMA agents with particular attention to [^99mTc]Tc-PSMA-i. The chemical and pharmacological properties of the latter will be compared and discussed, highlighting the pros and cons with respect to [⁶⁸Ga]Ga-PSMA11.     

Immobilization of the Gas Signaling Molecule H2S by Radioisotopes: Detection,Quantification, and In Vivo Imaging

Hydrogen sulfide (H₂S) has multifunctional roles as a gas signaling molecule in living systems. However, the efficient detection and imaging of H₂S in live animals is very challenging. Herein, we report the first radioisotope‐based immobilization technique for the detection, quantification, and in vivo imaging of endogenous H₂S. Macrocyclic ⁶⁴Cu complexes that instantly reacted with gaseous H₂S to form insoluble ⁶⁴CuS in a highly sensitive and selective manner were prepared. The H₂S concentration in biological samples was measured by a thin‐layer radiochromatography method. When ⁶⁴Cu–cyclen was injected into mice, an elevated H₂S concentration in the inflamed paw was clearly visualized and quantified by Cerenkov luminescence and positron emission tomography (PET) imaging. PET imaging was also able to pinpoint increased H₂S levels in a millimeter‐sized infarcted lesion of the rat heart.     

Polymeric Nanoparticles with a Glutathione‐Sensitive Heterodimeric Multifunctional Prodrug for In Vivo Drug Monitoring and Synergistic Cancer Therapy

Polymeric micelle‐based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. A polymeric nanomedicine has now been engineered that possesses an ultrahigh loading (59 %) of a glutathione (GSH)‐sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co‐deliver two synergistic drugs to tumors. An HDMP comprising of chemotherapeutic camptothecin (CPT) and photosensitizer 2‐(1‐hexyloxyethyl)‐2‐devinyl pyropheophorbide‐α (HPPH) was conjugated via a GSH‐cleavable linkage. The intrinsic fluorogenicity and label‐free radio‐chelation (⁶⁴Cu) of HPPH enabled direct drug monitoring by fluorescence imaging and positron emission tomography (PET). Through quantitative PET imaging, HDMP significantly improves drug delivery to tumors. The high synergistic therapeutic efficacy of HDMP‐loaded NPs highlights the rational design of HDMP, and presents exciting opportunities for polymer NP‐based drug delivery.     

Fluorine-18 Labelled Radioligands for PET Imaging of Cyclooxygenase-2

Molecular imaging probes enable the early and accurate detection of disease-specific biomarkers and facilitate personalized treatment of many chronic diseases, including cancer. Among current clinically used functional imaging modalities, positron emission tomography (PET) plays a significant role in cancer detection and in monitoring the response to therapeutic interventions. Several preclinical and clinical studies have demonstrated the crucial involvement of cyclooxygenase-2 (COX-2) isozyme in cancer development and progression, making COX-2 a promising cancer biomarker. A variety of COX-2-targeting PET radioligands has been developed based on anti-inflammatory drugs and selective COX-2 inhibitors. However, many of those suffer from non-specific binding and insufficient metabolic stability. This article highlights examples of COX-2-targeting PET radioligands labelled with the short-lived positron emitter ¹⁸F, including radiosynthesis and PET imaging studies published in the last decade (2012–2021).     

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.     

Multimodal Functional Imaging for Cancer/Tumor Microenvironments Based on MRI,EPRI, and PET

Radiation therapy is one of the main modalities to treat cancer/tumor. The response to radiation therapy, however, can be influenced by physiological and/or pathological conditions in the target tissues, especially by the low partial oxygen pressure and altered redox status in cancer/tumor tissues. Visualizing such cancer/tumor patho-physiological microenvironment would be a useful not only for planning radiotherapy but also to detect cancer/tumor in an earlier stage. Tumor hypoxia could be sensed by positron emission tomography (PET), electron paramagnetic resonance (EPR) oxygen mapping, and in vivo dynamic nuclear polarization (DNP) MRI. Tissue oxygenation could be visualized on a real-time basis by blood oxygen level dependent (BOLD) and/or tissue oxygen level dependent (TOLD) MRI signal. EPR imaging (EPRI) and/or T₁-weighted MRI techniques can visualize tissue redox status non-invasively based on paramagnetic and diamagnetic conversions of nitroxyl radical contrast agent. ¹³C-DNP MRI can visualize glycometabolism of tumor/cancer tissues. Accurate co-registration of those multimodal images could make mechanisms of drug and/or relation of resulted biological effects clear. A multimodal instrument, such as PET-MRI, may have another possibility to link multiple functions. Functional imaging techniques individually developed to date have been converged on the concept of theranostics.     

Introduction to Infrared and Raman-Based Biomedical Molecular Imaging and Comparison with Other Modalities

Molecular imaging has rapidly developed to answer the need of image contrast in medical diagnostic imaging to go beyond morphological information to include functional differences in imaged tissues at the cellular and molecular levels. Vibrational (infrared (IR) and Raman) imaging has rapidly emerged among the molecular imaging modalities available, due to its label-free combination of high spatial resolution with chemical specificity. This article presents the physical basis of vibrational spectroscopy and imaging, followed by illustration of their preclinical in vitro applications in body fluids and cells, ex vivo tissues and in vivo small animals and ending with a brief discussion of their clinical translation. After comparing the advantages and disadvantages of IR/Raman imaging with the other main modalities, such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography/single-photon emission-computed tomography (PET/SPECT), ultrasound (US) and photoacoustic imaging (PAI), the design of multimodal probes combining vibrational imaging with other modalities is discussed, illustrated by some preclinical proof-of-concept examples.     

A practical guide to the construction of radiometallated bioconjugates for positron emission tomography

Positron emission tomography (PET) has become a vital imaging modality in the diagnosis and treatment of disease, most notably cancer. A wide array of small molecule PET radiotracers have been developed that employ the short half-life radionuclides (11)C, (13)N, (15)O, and (18)F. However, PET radiopharmaceuticals based on biomolecular targeting vectors have been the subject of dramatically increased research in both the laboratory and the clinic. Typically based on antibodies, oligopeptides, or oligonucleotides, these tracers have longer biological half-lives than their small molecule counterparts and thus require labeling with radionuclides with longer, complementary radioactive half-lives, such as the metallic isotopes (64)Cu, (68)Ga, (86)Y, and (89)Zr. Each bioconjugate radiopharmaceutical has four component parts: biomolecular vector, radiometal, chelator, and covalent link between chelator and biomolecule. With the exception of the radiometal, a tremendous variety of choices exists for each of these pieces, and a plethora of different chelation, conjugation, and radiometallation strategies have been utilized to create agents ranging from (68)Ga-labeled pentapeptides to (89)Zr-labeled monoclonal antibodies. Herein, the authors present a practical guide to the construction of radiometal-based PET bioconjugates, in which the design choices and synthetic details of a wide range of biomolecular tracers from the literature are collected in a single reference. In assembling this information, the authors hope both to illuminate the diverse methods employed in the synthesis of these agents and also to create a useful reference for molecular imaging researchers both experienced and new to the field.     

新型核素~(64)Cu标记硝基咪唑类肿瘤乏氧显像剂及正电子发射断层扫描显像研究

采用新型核素64Cu标记了含丙烯胺肟[Pn AO(3,3,9,9-Tetramethyl-4,8-diazaundecane-2,10-dione Dioxime)]结构的硝基咪唑类乏氧显像剂Pn AO-1-(2-nitroimidazole)[BMS181321],通过优化反应条件,于室温下反应10 min后即得到高放化纯度和高比活度的标记化合物64Cu-BMS181321.目标产物经放射性高效液相色谱检测验证和体外稳定性实验确认后,通过尾静脉注射到人源胰腺癌(PANC-1细胞系)裸鼠体内,分别于注射显像剂4和8 h后进行小动物正电子发射断层扫描显像(Micro-PET).结果表明,4 h左右肿瘤乏氧区域有良好的放射性浓聚.64Cu-BMS181321的合成及其分子显像研究开创了64Cu标记硝基咪唑类乏氧显像剂进行乏氧显像的先例,经进一步药物临床实验评价后,64Cu-BMS181321有望成为具有良好前景的PET乏氧显像药物.