Fluorescent, phosphorescent, magnetic resonance contrast and radioactive tracer labelling of extracellular vesicles.

This review focusses on the significance of fluorescent, phosphorescent labelling and tracking of extracellular vesicles (EVs) for unravelling their biology, pathophysiology, and potential diagnostic and therapeutic uses. Various labeling strategies, such as lipid membrane, surface protein, luminal, nucleic acid, radionuclide, quantum dot labels, and metal complex-based stains, are evaluated for visualizing and characterizing EVs. Direct labelling with fluorescent lipophilic dyes is simple but generally lacks specificity, while surface protein labelling offers selectivity but may affect EV-cell interactions. Luminal and nucleic acid labelling strategies have their own advantages and challenges. Each labelling approach has strengths and weaknesses, which require a suitable probe and technique based on research goals, but new tetranuclear polypyridylruthenium(II) complexes as phosphorescent probes have strong phosphorescence, selective staining, and stability. Future research should prioritize the design of novel fluorescent probes and labelling platforms that can significantly enhance the efficiency, accuracy, and specificity of EV labeling, while preserving their composition and functionality. It is crucial to reduce false positive signals and explore the potential of multimodal imaging techniques to gain comprehensive insights into EVs.

"AquaF" Building Blocks for Water-Compatible SN2 18F-Fluorination of Small-Molecule Radiotracers.

Despite the widespread use of hydrophilic building blocks to incorporate 18F and improve tracer pharmacokinetics, achieving effective leaving group-mediated nucleophilic 18F-fluorination in water (excluding 18F/19F-exchange) remains a formidable challenge. Here, we present a water-compatible SN2 leaving group-mediated 18F-fluorination method employing preconjugated "AquaF" (phosphonamidic fluorides) building blocks. Among 19 compact tetracoordinated pentavalent P(V)-F candidates, the "AquaF" building blocks exhibit superior water solubility, sufficient capacity for 18F-fluorination in water, and excellent in vivo metabolic properties. Two nitropyridinol leaving groups, identified from a pool of leaving group candidates that further enhance the precursor water solubility, enable 18F-fluorination in water with a 10-2 M-1 s-1 level reaction rate constant (surpassing the 18F/19F-exchange) at room temperature. With the exergonic concerted SN2 18F-fluorination mechanism confirmed, this 18F-fluorination method achieves ∼90% radiochemical conversions and reaches a molar activity of 175 ± 40 GBq/µmol (using 12.2 GBq initial activity) in saline for 12 "AquaF"-modified proof-of-concept functional substrates and small-molecule 18F-tracers. [18F]AquaF-Flurpiridaz demonstrates significantly improved radiochemical yield and molar activity compared to 18F-Flurpiridaz, alongside enhanced cardiac uptake and heart/liver ratio in targeted myocardial perfusion imaging, providing a comprehensive illustration of "AquaF" building blocks-assisted water-compatible SN2 18F-fluorination of small-molecule radiotracers.

Fibroblast Activation Protein Inhibitor Tracers and Their Preclinical, Translational, and Clinical Status in China.

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.

Melanin-Targeting Radiotracers and Their Preclinical, Translational, and Clinical Status: From Past to Future.

Melanin is one of the representative biomarkers of malignant melanoma and a potential target for diagnosis and therapy. With advancements in chemistry and radiolabeling technologies, promising strides have been made to synthesize radiolabeled melanin-binding molecules for various applications. We present an overview of melanin-targeted radiolabeled molecules and compare their features reported in preclinical studies. Clinical practice and trials are also discussed to elaborate on the safety and validity of the probes, and expanded applications beyond melanoma are reviewed. Melanin-targeted imaging holds potential value in the diagnosis, staging, and prognostic assessment of melanoma and other applications. Melanin-targeted radionuclide therapy possesses immense potential but requires more clinical validation. Furthermore, an intriguing avenue for future research involves expanding the application scope of melanin-targeted probes and exploring their value.

Recent Advances in Radiotracers Targeting Novel Cancer-Specific Biomarkers in China: A Brief Overview.

Radiopharmaceuticals play a critical role in nuclear medicine, providing novel tools for specifically delivering radioisotopes for the diagnosis and treatment of cancers. As the starting point for developing radiopharmaceuticals, cancer-specific biomarkers are important and receive worldwide attention. This field in China is currently experiencing a rapid expansion, with multiple radiotracers targeting novel targets being developed and translated into clinical studies. This review provides a brief overview of the exploration of novel imaging targets, preclinical evaluation of their targeting ligands, and translational research in China from 2020 to 2023, for detecting cancer, guiding targeted therapy, and visualizing the immune microenvironment. We believe that China will play an even more important role in the development of nuclear medicine in the world in the future.

Development and first-in-human study of PSMA-targeted PET tracers with improved pharmacokinetic properties.

PURPOSE: A series of new 68Ga-labeled tracers based on [68Ga]Ga-PSMA-617 were developed to augment the tumor-to-kidney ratio and reduce the activity accumulation in bladder, ultimately minimize radiation toxicity to the urinary system. METHODS: We introduced quinoline group, phenylalanine and decanoic acid into different tracers to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Their binding affinity onto LNCaP cells was determined through in vitro saturation assays and competition binding assays. In vivo metabolic study, PET imaging and biodistribution experiment were performed in LNCaP tumor-bearing B-NSG male mice. The most promising tracer was selected for first-in-human study. RESULTS: Four radiotracers were synthesized with radiochemical purity (RCP) > 95% and molar activity in a range of 20.0-25.5 GBq/µmol. The binding affinities (Ki) of TWS01, TWS02 to PSMA were in the low nanomolar range (< 10 nM), while TWS03 and TWS04 exhibited binding affinities with Ki > 20 nM (59.42 nM for TWS03 and 37.14 nM for TWS04). All radiotracers exhibited high stability in vivo except [68Ga]Ga-TWS03. Micro PET/CT imaging and biodistribution analysis revealed that [68Ga]Ga-TWS02 enabled clear tumor visualization in PET images at 1.5 h post-injection, with higher tumor-to-kidney ratio (T/K, 0.93) and tumor-to-muscle ratio (T/M, 107.62) compared with [68Ga]Ga-PSMA-617 (T/K: 0.39, T/M: 15.01) and [68Ga]Ga-PSMA-11 (T/K: 0.15, T/M: 24.00). In first-in-human study, [68Ga]Ga-TWS02 effectively detected PCa-associated lesions including primary and metastatic lesions, with lower accumulation in urinary system, suggesting that [68Ga]Ga-TWS02 might be applied in the detection of bladder invasion, with minimized radiation toxicity to the urinary system. CONCLUSION: Introduction of quinoline group, phenylalanine and decanoic acid into different tracers can modulate the binding affinity and pharmacokinetics of PSMA in vivo. [68Ga]Ga-TWS02 showed high binding affinity to PSMA, excellent pharmacokinetic properties and clear imaging of PCa-associated lesions, making it a promising radiotracer for the clinical diagnosis of PCa. Moreover, TWS02 with a chelator DOTA could also label 177Lu and 225Ac, which could be used for PCa treatment without significant side effects. TRIAL REGISTRATION: The clinical evaluation of this study was registered On October 30, 2021 at https://www.chictr.org.cn/ (No: ChiCTR2100052545).

Synthesis and preclinical evaluation of novel 18F-vancomycin-based tracers for the detection of bacterial infections using positron emission tomography.

INTRODUCTION: Bacterial infections are a major problem in medicine, and the rapid and accurate detection of such infections is essential for optimal patient outcome. Bacterial infections can be diagnosed by nuclear imaging, but most currently available modalities are unable to discriminate infection from sterile inflammation. Bacteria-targeted positron emission tomography (PET) tracers have the potential to overcome this hurdle. In the present study, we compared three 18F-labelled PET tracers based on the clinically applied antibiotic vancomycin for targeted imaging of Gram-positive bacteria. METHODS: [18F]FB-NHS and [18F]BODIPY-FL-NHS were conjugated to vancomycin. The resulting conjugates, together with our previously developed [18F]PQ-VE1-vancomycin, were tested for stability, lipophilicity, selective binding to Gram-positive bacteria, antimicrobial activity and biodistribution. For the first time, the pharmacokinetic properties of all three tracers were compared in healthy animals to identify potential binding sites. RESULTS: [18F]FB-vancomycin, [18F]BODIPY-FL-vancomycin, and [18F]PQ-VE1-vancomycin were successfully synthesized with radiochemical yields of 11.7%, 2.6%, and 0.8%, respectively. [18F]FB-vancomycin exhibited poor in vitro and in vivo stability and, accordingly, no bacterial binding. In contrast, [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin showed strong and specific binding to Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which was outcompeted by unlabeled vancomycin only at concentrations exceeding clinically relevant vancomycin blood levels. Biodistribution showed renal clearance of [18F]PQ-VE1-vancomycin and [18F]BODIPY-FL-vancomycin with low non-specific accumulation in muscles, fat and bones. CONCLUSION: Here we present the synthesis and first evaluation of the vancomycin-based PET tracers [18F]BODIPY-FL-vancomycin and [18F]PQ-VE1-vancomycin for image-guided detection of Gram-positive bacteria. Our study paves the way towards real-time bacteria-targeted diagnosis of soft tissue and implant-associated infections that are oftentimes caused by Gram-positive bacteria, even after prophylactic treatment with vancomycin.

Noninvasive measurement of tracer extraction efficiency in tissue, illustrated with Tc-99m-MAG3.

OBJECTIVE: The aim of this study is to develop a noninvasive technique for measuring tissue tracer extraction efficiency ( E ) and illustrate it for Tc-99m-mercaptoacetyltriglycine (MAG3) and kidney. METHODS: E was measured in 10 patients with normal MAG3 renography. E is the ratio of tissue clearance-to-blood flow ( Ki/F ). For single-photon tracers, attenuation constants are unknown, so Ki and F cannot be separately measured. However, by deriving attenuation-uncorrected Ki' and F' from the same regions of interests (ROIs), these constants cancel out, giving E . Using a lung ROI for blood activity, F was measured from first-pass and Ki' from Gjedde-Patlak-Rutland (GPR) analysis up to 130 s. Because of interference from right ventricle, a left ventricular ROI (LV) is unsuitable for F' but was used in GPR analysis, making an adjustment for the ratio of respective blood pool signals arising from lung and LV ROIs in early frames (60-90 s). RESULTS: A lung ROI underestimates F' by 4% at normal LV function. Chest wall interstitial activity ( I ), which does not affect F' , amounted to 53 and 30% of the lung and LV signals at 20 min, and 12 and 6% at 130 s, resulting in underestimations of Ki of 4 and 2%, respectively. Ignoring these opposing errors, E based on lung ROI for left and right kidneys was 43.5 (SD 8)% and 47.3 (9)%, and based on LV ROI for GPR analysis was 44.5 (10.9)% and 48.3 (10.6)%. CONCLUSION: E can be measured by combining blood flow from first-pass with clearance from GPR analysis, and has potential value both clinically and in clinical research.

Homodimeric peptide radiotracer [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 imaging of cervical cancer patients.

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 [68Ga]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 (PEG4) and triglyicine (Gly3) spacer, and labeled with 68Ga, to construct [68Ga]Ga-NOTA-(TMVP1)2. Binding of VEGFR-3 by TMVP1 and (TMVP1)2, respectively, was modeled by molecular docking. The affinity of [68Ga]Ga-NOTA-(TMVP1)2 for VEGFR-3 and its ability to bind to cells were evaluated. MicroPET imaging and biodistribution studies of [68Ga]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 [68Ga]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. [68Ga]Ga-NOTA-(TMVP1)2 was excreted mainly through the renal route and partly through the liver route. In mice bearing C33A xenografts, [68Ga]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 [68Ga]Ga-NOTA-(TMVP1)2 in tumors (0.58 ± 0.01% ID/g). [68Ga]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 [18F]-FDG identified lesions (18/22, 81.8%) showed moderate to high signal intensity on [68Ga]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 [68Ga]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).

Synthesis, preclinical, and initial clinical evaluation of integrin αVß3 and gastrin-releasing peptide receptor (GRPR) dual-targeting radiotracer [68Ga]Ga-RGD-RM26-03.

Integrin receptor αvß3 and gastrin-releasing peptide receptor (GRPR) expression of tumors could be detected using PET imaging with radiolabeled Arg-Gly-Asp (RGD) and the antagonistic bombesin analog RM26, respectively. The purpose of this study was to investigate the dual receptor-targeting property of the heterodimer RGD-RM26-03 (denoted as LNC1015), demonstrate the tumor diagnostic value of [68Ga]Ga-LNC1015 in preclinical experiments, and evaluate its preliminary clinical feasibility. METHODS: LNC1015 was designed and synthesized by linking cyclic RGD and the RM26 peptide. Preclinical pharmacokinetics were detected in a PC3 xenograft model using microPET and biodistribution studies. The clinical feasibility of [68Ga]Ga-LNC1015 PET/CT was performed in patients with breast cancer, and the results were compared with those of 18F-fluorodeoxyglucose (FDG). RESULTS: [68Ga]Ga-LNC1015 had good stability in saline for at least 2 h, and favorable binding affinity and specificity were demonstrated in vitro and in vivo. The tumor uptake and retention of [68Ga]Ga-LNC1015 during PET imaging were improved compared with its monomeric counterparts [68Ga]Ga-RGD and [68Ga]Ga-RM26 at all the time points examined. In our initial clinical studies, the tumor uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in [68Ga]Ga-LNC1015 PET/CT were significantly higher than those in [18F]FDG PET/CT, resulting in high lesion detection rate and tumor delineation. CONCLUSION: The dual targeting radiotracer [68Ga]Ga-LNC1015 showed significantly improved tumor uptake and retention, as well as lower liver uptake than [68Ga]Ga-RGD and [68Ga]Ga-RM26 monomer. The first-in-human study showed high TBRs in patients, suggesting favorable pharmacokinetics and high clinical feasibility for PET/CT imaging of cancer.

A bis-boron boramino acid PET tracer for brain tumor diagnosis.

PURPOSE: Boramino acids are a class of amino acid biomimics that replace the carboxylate group with trifluoroborate and can achieve the 18F-labeled positron emission tomography (PET) and boron neutron capture therapy (BNCT) with identical chemical structure. METHODS: This study reports a trifluoroborate-derived boronophenylalanine (BBPA), a derived boronophenylalanine (BPA) for BNCT, as a promising PET tracer for tumor imaging. RESULTS: Competition inhibition assays in cancer cells suggested the cell accumulation of [18F]BBPA is through large neutral amino acid transporter type-1 (LAT-1). Of note, [18F]BBPA is a pan-cancer probe that shows notable tumor uptake in B16-F10 tumor-bearing mice. In the patients with gliomas and metastatic brain tumors, [18F]BBPA-PET shows good tumor uptake and notable tumor-to-normal brain ratio (T/N ratio, 18.7 ± 5.5, n = 11), higher than common amino acid PET tracers. The [18F]BBPA-PET quantitative parameters exhibited no difference in diverse contrast-enhanced status (P = 0.115-0.687) suggesting the [18F]BBPA uptake was independent from MRI contrast-enhancement. CONCLUSION: This study outlines a clinical trial with [18F]BBPA to achieve higher tumor-specific accumulation for PET, provides a potential technique for brain tumor diagnosis, and might facilitate the BNCT of brain tumors.

Peptidic heterodimer-based radiotracer targeting fibroblast activation protein and integrin αvß3.

PURPOSE: Several studies have demonstrated the advantages of heterodimers over their corresponding monomers due to the multivalency effect. This effect leads to an increased number of effective targeted receptors and, consequently, improved tumor uptake. Fibroblast activation protein (FAP) and integrin αvß3 are found to be overexpressed in different components of the tumor microenvironment. In our pursuit of enhancing tumor uptake and retention, we designed and developed a novel peptidic heterodimer that synergistically targets both FAP and integrin αvß3. METHODS: FAP-RGD was synthesized from FAP-2286 and c(RGDfK) through a multi-step organic synthesis. The dual receptor binding property of 68Ga-FAP-RGD was investigated by cell uptake and competitive binding assays. Preclinical pharmacokinetics were determined in HT1080-FAP and U87MG tumor models using micro-positron emission tomography/computed tomography (micro-PET/CT) and biodistribution studies. The antitumor efficacy of 177Lu-FAP-RGD was assessed in U87MG tumor models. The radiation exposure and clinical diagnostic performance of 68 Ga-FAP-RGD were evaluated in healthy volunteers and cancer patients. RESULTS: Bi-specific radiotracer 68Ga-FAP-RGD exhibited high binding affinity for both FAP and integrin αvß3. In comparison to 68Ga-FAP-2286 and 68Ga-RGDfK, 68Ga-FAP-RGD displayed enhanced tumor uptake and longer tumor retention time in preclinical models. 177Lu-FAP-RGD could efficiently suppress the growth of U87MG tumor in vivo when applied at an activity of 18.5 and 29.6 MBq. The effective dose of 68Ga-FAP-RGD was 1.06 × 10-2 mSv/MBq. 68Ga-FAP-RGD demonstrated low background activity and stable accumulation in most neoplastic lesions up to 3 h. CONCLUSION: Taking the advantages of multivalency effect, the bi-specific radiotracer 68Ga-FAP-RGD showed superior tumor uptake and retention compared to its corresponding monomers. Preclinical studies with 68Ga- or 177Lu-labeled FAP-RGD showed favorable image contrast and effective antitumor responses. Despite the excellent performance of 68Ga-FAP-RGD in clinical diagnosis, experimental efforts are currently underway to optimize the structure of FAP-RGD to increase its potential for clinical application in endoradiotherapy.

Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir.

Positron emission tomography (PET) imaging allows monitoring the progression of amyloid aggregation in the living brain. [18F]-Flortaucipir is the only approved PET tracer compound for the visualisation of tau aggregation. Here, we describe cryo-EM experiments on tau filaments in the presence and absence of flortaucipir. We used tau filaments isolated from the brain of an individual with Alzheimer's disease (AD), and from the brain of an individual with primary age-related tauopathy (PART) with a co-pathology of chronic traumatic encephalopathy (CTE). Unexpectedly, we were unable to visualise additional cryo-EM density for flortaucipir for AD paired helical or straight filaments (PHFs or SFs), but we did observe density for flortaucipir binding to CTE Type I filaments from the case with PART. In the latter, flortaucipir binds in a 1:1 molecular stoichiometry with tau, adjacent to lysine 353 and aspartate 358. By adopting a tilted geometry with respect to the helical axis, the 4.7 Å distance between neighbouring tau monomers is reconciled with the 3.5 Å distance consistent with π-π-stacking between neighbouring molecules of flortaucipir.

Feasibility of intraoperative injection of radioactive tracer and blue dye for sentinel lymph node biopsy in vulvar cancer.

OBJECTIVE: The objective of this study was to examine the feasibility and success rate of intraoperative injection of radiotracer and blue dye performed by the surgeon without the use of preoperative lymphoscintigraphy for the detection of sentinel lymph nodes in clinically early stage vulvar cancer. METHODS: All patients with clinically early stage vulvar cancer who underwent attempted sentinel lymph node biopsy using intraoperative injection of Technetium-99 m (99mTc) tracer and blue dye performed by the surgeon after induction of anesthesia at single academic institution from 12/2009 to 5/2022 were identified. Demographic and clinicopathologic variables were collected. Data were compared using descriptive statistics. RESULTS: One hundred sixty-four patients (median age 66.4 years) underwent intraoperative injection of radioactive tracer and dye for sentinel lymph node biopsy. Most patients (n = 156, 95.1%) were white. Squamous cell carcinoma accounted for 138 cases (84.1%), melanoma for 10 (6.1%), extra-mammary invasive Paget's disease for 11 (6.7%), and other histologies for 5 (3%). A majority of cases were stage I disease on final pathology (n = 119, 72.6%). Most patients (n = 117, 71%) had tumors located within 2 cm of the midline and underwent planned bilateral groin assessment, while 47 (29%) had well lateralized lesions and underwent unilateral groin assessment. For the patients undergoing unilateral groin assessment, 44 of 47 (93.6%) had successful unilateral mapping. Of the patients who underwent bilateral groin assessment, 87 of 117 (74.4%) had successful bilateral mapping, and 26 of 117 (22.2%) had successful unilateral mapping. Of the 26 patients who underwent bilateral assessment but only had unilateral mapping, 19 had unilateral mapping to ipsilateral groin but failed contralateral mapping, six had midline lesions with successful mapping to one groin but failed mapping to the other groin, and one had unilateral mapping to the contralateral groin but not ipsilateral groin. The total successful sentinel lymph node mapping rate in this cohort was 86.5% (243/281 total sentinel lymph node attempts). CONCLUSION: In this cohort, the overall success rate of sentinel lymph node mapping and biopsy was 86.5%. The high rate of successful sentinel lymph node mapping supports the use of intraoperative radiotracer and blue dye injection by trained providers.

Airway clearance techniques compared to no airway clearance techniques for cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is an inherited progressive life-limiting disease characterised by the build-up of abnormally thick, sticky mucus affecting mostly the lungs, pancreas, and digestive system. Airway clearance techniques (ACTs), traditionally referred to as chest physiotherapy, are recommended as part of a complex treatment programme for people with CF. The aim of an ACTs is to enhance mucociliary clearance and remove viscous secretions from the airways within the lung to prevent distal airway obstruction. This reduces the infective burden and associated inflammatory effects on the airway epithelia.  There are a number of recognised ACTs, none of which have shown superiority in improving short-term outcomes related to mucus transport. This systematic review, which has been updated regularly since it was first published in 2000, considers the efficacy of ACTs compared to not performing any ACT in adults and children with CF. It is important to continue to review this evidence, particularly the long-term outcomes, given the recent introduction of highly effective modulator therapies and the improved health outcomes and potential changes to CF management associated with these drugs. OBJECTIVES: To determine the effectiveness and acceptability of airway clearance techniques compared to no airway clearance techniques or cough alone in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings, to 17 October 2022. We searched ongoing trials registers (Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform) to 7 November 2022. SELECTION CRITERIA: We included randomised or quasi-randomised studies that compared airway clearance techniques (chest physiotherapy) with no airway clearance techniques or spontaneous cough alone in people with CF. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed study eligibility, extracted data, and assessed the risk of bias of the included studies. We used GRADE methodology to assess the certainty of the evidence. MAIN RESULTS: We included 11 cross-over studies (153 participants) and one parallel study (41 participants). There were differences between studies in how the interventions were delivered, with several intervention groups combining more than one ACT. One study used autogenic drainage; five used conventional chest physiotherapy; nine used positive expiratory pressure (PEP), with one study varying the water pressure between arms; three studies used oscillating PEP; two used exercise; and two used high-frequency chest wall oscillation (HFCWO). Of the 12 included studies, 10 were single-treatment studies, and two delivered the intervention over two consecutive days (once daily in one study, twice daily in the second). This substantial heterogeneity in the treatment interventions precluded pooling of data for meta-analysis. Blinding of participants, caregivers, and clinicians is impossible in airway clearance studies; we therefore judged all studies at unclear risk of performance bias. Lack of information in eight studies made assessment of risk of bias unclear for most other domains.  We rated the certainty of evidence as low or very low due to the short-term cross-over trial design, small numbers of participants, and uncertain risk of bias across most or all domains. Six studies (84 participants) reported no effect on pulmonary function variables following intervention; but one study (14 participants) reported an improvement in pulmonary function following the intervention in some of the treatment groups. Two studies reported lung clearance index: one (41 participants) found a variable response to treatment with HFCWO, whilst another (15 participants) found no effect on lung clearance index with PEP therapy (low-certainty evidence). Five studies (55 participants) reported that ACTs, including coughing, increased radioactive tracer clearance compared to control, while a further study (eight participants) reported no improvement in radioactive tracer clearance when comparing PEP to control, although coughing was discouraged during the PEP intervention. We rated the certainty of evidence on the effect of ACTs on radioactive tracer clearance as very low. Four studies (46 participants) investigated the weight of mucus cleared from the lungs and reported greater secretions during chest physiotherapy compared to a control. One study (18 participants) reported no differences in sputum weight (very low-certainty evidence). AUTHORS' CONCLUSIONS: The evidence from this review shows that ACTs may have short-term effects on increasing mucus transport in people with CF. All included studies had short-term follow-up; consequently, we were unable to draw any conclusions on the long-term effects of ACTs compared to no ACTs in people with CF. The evidence in this review represents the use of airway clearance techniques in a CF population before widespread use of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Further research is needed to determine the effectiveness and acceptability of airway clearance in those treated with highly effective CFTR modulators.

Radionuclide Tracers for Myocardial Perfusion Imaging and Blood Flow Quantification.

Myocardial perfusion imaging by nuclear cardiology is widely validated for the diagnosis, risk stratification, and management of patients with suspected or known coronary artery disease. Numerous radiopharmaceuticals are available for single-photon emission computed tomography and PET modalities. Each tracer shows advantages and limitations that should be taken into account in performing an imaging examination. This review aimed to summarize the state-of-the-art radiotracers used for myocardial perfusion imaging and blood flow quantification, highlighting the new technologic advances and promising possible applications.

α-D-Glucose as a non-radioactive MRS tracer for metabolic studies of the brain.

Changes in brain glucose metabolism occur in many neurological disorders as well as during aging. Most studies on the uptake of glucose in the brain use positron emission tomography, which requires injection of a radioactive tracer. Our study shows that ultra-high-field 1H-MRS can be used to measure α-D-glucose at 5.22 ppm in vivo, and the α-D-glucose can be used as a radiation-free tracer in the human brain.

Partial Response Upon Peptide Receptor Radionuclide Therapy in a Highly Proliferative Pancreatic Neuroendocrine Tumor.

ABSTRACT: We report on a patient diagnosed with an aggressive pancreatic neuroendocrine tumor (NET G3; Ki67 = 60%), who underwent pancreatic resection with partial removal of liver lesions. The patient refused chemotherapy. Dual-tracer imaging with 18 F-FDG and somatostatin receptor (SSTR)-targeted PET/CT was conducted. Radiotracer accumulation on both imaging modalities in bilobar hepatic lesions was observed. "Cold" somatostatin analogues with four cycles of peptide receptor radionuclide therapy (PRRT) were initiated, leading to partial response. Even in highly proliferative but differentiated G3 NET (Ki67>55%), SSTR expression in sites of disease should be evaluated, which may then allow PRRT, even as first-line systemic treatment.

Recent Advances in Bioorthogonal Click Chemistry for Enhanced PET and SPECT Radiochemistry.

Due to their high reaction rate and reliable selectivity, bioorthogonal click reactions have been extensively investigated in numerous research fields, such as nanotechnology, drug delivery, molecular imaging, and targeted therapy. Previous reviews on bioorthogonal click chemistry for radiochemistry mainly focus on 18F-labeling protocols employed to produce radiotracers and radiopharmaceuticals. In fact, besides fluorine-18, other radionuclides such as gallium-68, iodine-125, and technetium-99m are also used in the field of bioorthogonal click chemistry. Herein, to provide a more comprehensive perspective, we provide a summary of recent advances in radiotracers prepared using bioorthogonal click reactions, including small molecules, peptides, proteins, antibodies, and nucleic acids as well as nanoparticles based on these radionuclides. The combination of pretargeting with imaging modalities or nanoparticles, as well as the clinical translations study, are also discussed to illustrate the effects and potential of bioorthogonal click chemistry for radiopharmaceuticals.