Search Results (53)

L-3-[¹⁸F]-fluoro-α-methyl tyrosine ([¹⁸F]FAMT) is an amino acid positron emission tomography (PET) tracer with high specificity for malignant tumors through its selective transport via L-type amino acid transporter (LAT) 1. Although extensively studied for its diagnostic performance, a comprehensive review of its molecular and clinical characteristics remains lacking. A systematic literature review (1997–2025) was conducted using PubMed and Web of Science, with keywords including “L-3-[¹⁸F]-fluoro-α-methyl tyrosine”, “[¹⁸F]FAMT”, “amino acid PET”, and “tumor imaging”. The review covered aspects of synthesis, structural properties, pharmacokinetics, and clinical applications. Notably, while research on [¹⁸F]FAMT has declined significantly in recent years, [¹⁸F]FAMT PET demonstrates superior specificity to [¹⁸F]FDG PET in distinguishing malignancies from inflammatory lesions and offers distinct advantages in lung, esophageal, and oral cancers, though with slightly lower sensitivity. Its key features include tumor-specific uptake patterns, rapid blood clearance, and a significant correlation between its uptake levels and both LAT1 expression and tumor proliferation. In conclusion, [¹⁸F]FAMT is a promising PET tracer with notable advantages in tumor imaging, particularly due to its LAT1 selectivity and favorable pharmacokinetics. Despite challenges in production, these characteristics underscore its clinical value in cancers requiring precise imaging. Future research should focus on optimizing synthesis, expanding clinical validation, and exploring theranostic applications. Full article

Tryptophan (Trp)-based radiotracers have excellent potential for imaging many different types of brain pathology because of their involvement with both the serotonergic and kynurenine (KYN) pathways. However, radiotracers specific to the kynurenine metabolism pathway are limited. In addition, historically Trp-based radiopharmaceuticals were synthesized with the short-lived isotope carbon-11. A newer generation of Trp-based imaging agents using the longer half-lived and commercially available isotopes, such as fluorine-18 and iodine-124, are being developed. The newly developed amino acid-based tracers have been demonstrated to have favorable radiochemical and imaging characteristics in pre-clinical studies. However, many barriers still exist in the clinical translation of KYN pathway-specific radiotracers. Full article

11C-Methionine (MET) is a widely utilized amino acid tracer in positron emission tomography (PET) imaging of primary brain tumors. 11C-MET PET offers valuable insights for tumor classification, facilitates treatment planning, and aids in monitoring therapeutic response. Its tracer properties allow better delineation of the active tumor volume, even in regions that show no contrast enhancement on conventional magnetic resonance imaging (MRI). This review focuses on the role of MET-PET in brain glioma imaging. The introduction provides a brief clinical overview of the problems of high-grade and recurrent gliomas. It discusses glioma management, radiotherapy planning, and the difficulties of imaging after chemoradiotherapy (pseudoprogression or radionecrosis). The mechanism of MET-PET is described. Additionally, the review encompasses the application of MET-PET in the context of primary gliomas, addressing its diagnostic precision, utility in tumor classification, prognostic value, and role in guiding biopsy procedures and radiotherapy planning. Full article

Gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers and is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake and/or metabolic instability observed for most reported GRPR-targeted radioligands might limit their clinical applications. Our group recently reported a GRPR-targeted antagonist tracer, [⁶⁸Ga]Ga-TacsBOMB2 ([⁶⁸Ga]Ga-DOTA-Pip-D-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Leu¹³ψThz¹⁴-NH₂), which showed a minimal pancreas uptake in a preclinical mouse model. In this study, we synthesized four derivatives with unnatural amino acid substitutions (Tle¹⁰-derived Ga-LW01158, NMe-His¹²-derived Ga-LW01160, α-Me-Trp⁸- and Tle¹⁰-derived Ga-LW01186, and Tle¹⁰- and N-Me-Gly¹¹-derived Ga-LW02002) and evaluated their potential for detecting GRPR-expressing tumors with positron emission tomography (PET). The binding affinities (K_i(GRPR)) of Ga-LW01158, Ga-LW01160, Ga-LW01186, and Ga-LW02002 were 5.11 ± 0.47, 187 ± 17.8, 6.94 ± 0.95, and 11.0 ± 0.39 nM, respectively. [⁶⁸Ga]Ga-LW01158, [⁶⁸Ga]Ga-LW01186, and [⁶⁸Ga]Ga-LW02002 enabled clear visualization of subcutaneously implanted human prostate cancer PC-3 tumor xenografts in mice in PET images. Ex vivo biodistribution studies showed that [⁶⁸Ga]Ga-LW01158 had the highest tumor uptake (11.2 ± 0.65 %ID/g) and good tumor-to-background uptake ratios at 1 h post-injection. Comparable in vivo stabilities were observed for [⁶⁸Ga]Ga-LW01158, [⁶⁸Ga]Ga-LW01186, and [⁶⁸Ga]Ga-LW02002 (76.5–80.7% remaining intact in mouse plasma at 15 min post-injection). In summary, the Tle¹⁰ substitution, either alone or combined with α-Me-Trp⁸ or NMe-Gly¹¹ substitution, in Ga-TacsBOMB2 generates derivatives that retained good GRPR binding affinity and in vivo stability. With good tumor uptake and tumor-to-background imaging contrast, [⁶⁸Ga]Ga-LW01158 is promising for detecting GRPR-expressing lesions with PET. Full article

To better diagnose and treat tumors related to arginine metabolism, (2S,4S)-2-amino-4-(4-(2-(fluoro-¹⁸F)ethoxy)benzyl)-5-guanidinopentanoic acid ([¹⁸F]7) was designed and prepared by introducing [¹⁸F]fluoroethoxy benzyl on carbon-4 of arginine. [¹⁸F]7 and 7 were successfully prepared using synthesis methods similar to those used for (2S,4S)-4-[¹⁸F]FEBGln and (2S,4S)-4-FEBGln, respectively. In vitro experiments on cell transport mechanisms showed that [¹⁸F]7 was similar to (2S,4S)4-[¹⁸F]FPArg and was transported into tumor cells by cationic amino acid transporters. However, [¹⁸F]7 can also enter MCF-7 cells via ASC and ASC2 amino acid transporters. Further microPET-CT imaging showed that the initial uptake and retention properties of [¹⁸F]7 in MCF-7 subcutaneous tumors were good (2.29 ± 0.09%ID/g at 2.5 min and 1.71 ± 0.09%ID/g at 60 min after administration), without significant defluorination in vivo. However, compared to (2S,4S)4-[¹⁸F]FPArg (3.06 ± 0.59%ID/g at 60 min after administration), [¹⁸F]7 exhibited lower tumor uptake and higher nonspecific uptake. When further applied to U87MG imaging, [¹⁸F]7 can quickly visualize brain gliomas (tumor-to-brain, 1.85 at 60 min after administration). Therefore, based on the above results, [¹⁸F]7 will likely be applied for the diagnosis of arginine nutrition-deficient tumors and efficacy evaluations. Full article

Background: The occurrence of accidental nerve damage during surgery and the increasing application of image guidance during head-and-neck surgery have highlighted the need for molecular targeted nerve-sparing interventions. The implementation of such interventions relies on the availability of nerve-specific tracers. In this paper, we describe the development of a truncated peptide that has an optimized affinity for protein zero (P0), the most abundant protein in myelin. Methods and Materials: Further C- and N-terminal truncation was performed on the lead peptide Cy5-P0_101–125. The resulting nine Cy5-labelled peptides were characterized based on their photophysical properties, P0 affinity, and in vitro staining. These characterizations were combined with evaluation of the crystal structure of P0, which resulted in the selection of the optimized tracer Cy5-P0_112–125. A near-infrared Cy7-functionalized derivative (Cy7-P0_112–125) was used to perform an initial evaluation of fluorescence-guided surgery in a porcine model. Results: Methodological truncation of the 26-amino-acid lead compound Cy5-P0_101–125 resulted in a size reduction of 53.8% for the optimized peptide Cy5-P0_112–125. The peptide design and the 1.5-fold affinity gain obtained after truncation could be linked to interactions observed in the crystal structure of the extracellular portion of P0. The near-infrared analogue Cy7-P0_112–125 supported nerve illumination during fluorescence-guided surgery in the head-and-neck region in a porcine model. Conclusions: Methodological truncation yielded a second-generation P0-specific peptide. Initial surgical evaluation suggests that the peptide can support molecular targeted nerve imaging. Full article

Our aim was to provide a comprehensive overview of the existing literature concerning the clinical applications of positron emission computed tomography (PET) with radiopharmaceuticals targeting the translocator protein (TSPO) in gliomas. A literature search for studies about TSPO PET in the last 10 years (from 2013 to February 2023) was carried out on PubMed, Scopus, and Web of Science using the following keywords: “PET” AND “Gliomas” AND “TSPO”. The Critical Appraisal Skills Program checklist for diagnostic test studies was used for testing the quality of selected papers. Ten articles were selected, encompassing 314 glioma patients submitted to PET/CT (9/10) or PET/MRI (1/10) with TSPO ligands. Among the various available TSPO tracers, the most frequently used was the third-generation ligand, [¹⁸F]-GE-180. TSPO PET results were useful to identify anaplastic transformation in gliomas and for the prognostic stratification of patients bearing homogeneous genetic alterations. When compared to amino-acid PET, TSPO PET with [¹⁸F]-GE-180 presented superior image quality and provided larger and only partially overlapping PET-based volumes. Although biased by some issues (i.e., small sample size, most of the studies coming from the same country), preliminary applications of TSPO PET were encouraging. Further studies are needed to define implications in clinical practice and shape the role of TSPO PET for patients’ selection for potential TSPO-targeted molecular therapies. Full article

Cancer therapies use different compounds of synthetic and natural origin. However, despite some positive results, relapses are common, as standard chemotherapy regimens are not fully capable of completely eradicating cancer stem cells. While vinblastine is a common chemotherapeutic agent in the treatment of blood cancers, the development of vinblastine resistance is often observed. Here, we performed cell biology and metabolomics studies to investigate the mechanisms of vinblastine resistance in P3X63Ag8.653 murine myeloma cells. Treatment with low doses of vinblastine in cell media led to the selection of vinblastine-resistant cells and the acquisition of such resistance in previously untreated, murine myeloma cells in culture. To determine the mechanistic basis of this observation, we performed metabolomic analyses of resistant cells and resistant drug-induced cells in a steady state, or incubation with stable isotope-labeled tracers, namely, ¹³C ¹⁵N-amino acids. Taken together, these results indicate that altered amino acid uptake and metabolism could contribute to the acquisition of vinblastine resistance in blood cancer cells. These results will be useful for further research on human cell models. Full article

Purpose: A new PET radiotracer ¹⁸F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure–activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of ¹⁸F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer–NET interaction, whereby a T-shaped π–π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors. Full article

Adult-type diffuse gliomas are treated with a multimodality treatment approach that includes radiotherapy both in the primary setting, and in the case of progressive or recurrent disease. Radiation necrosis represents a major complication of radiotherapy. Recurrent disease and treatment-related changes are often indistinguishable using conventional imaging methods. The present systematic review aims at assessing the diagnostic role of PET imaging using different radiopharmaceuticals in differentiating radiation necrosis and disease relapse in irradiated adult-type diffuse gliomas. We conducted a comprehensive literature search using the PubMed/MEDLINE and EMBASE databases for original research studies of interest. In total, 436 articles were assessed for eligibility. Ten original papers, published between 2014 and 2022, were selected. Four articles focused on [¹⁸F]FDG, seven on amino acid tracers ([¹⁸F]FET n = 3 and [¹¹C]MET n = 4), one on [¹¹C]CHO, and one on [⁶⁸Ga]Ga-PSMA. Visual assessment, semi-quantitative methods, and radiomics were applied for image analysis. Furthermore, 2/10 papers were comparative studies investigating different radiopharmaceuticals. The present review, the first one on the topic in light of the new 2021 CNS WHO classification, highlighted the usefulness of PET imaging in distinguishing radiation necrosis and tumour recurrence, but revealed high heterogeneity among studies. Full article

Primary malignant brain tumors are heterogeneous and infrequent neoplasms. Their classification, therapeutic regimen and prognosis have undergone significant development requiring the innovation of an imaging diagnostic. The performance of enhanced magnetic resonance imaging depends on blood–brain barrier function. Several studies have demonstrated the advantages of static and dynamic amino acid PET/CT providing accurate metabolic status in the neurooncological setting. The aim of our single-center retrospective study was to test the primary diagnostic role of amino acid PET/CT compared to enhanced MRI. Emphasis was placed on cases prior to intervention, therefore, a certain natural bias was inevitable. In our analysis for newly found brain tumors ¹⁸F-FET PET/CT outperformed contrast MRI and PWI in terms of sensitivity and negative predictive value (100% vs. 52.9% and 36.36%; 100% vs. 38.46% and 41.67%), in terms of positive predictive value their performance was roughly the same (84.21 % vs. 90% and 100%), whereas regarding specificity contrast MRI and PWI were superior (40% vs. 83.33% and 100%). Based on these results the superiority of ¹⁸F-FET PET/CT seems to present incremental value during the initial diagnosis. In the case of non-enhancing tumors, it should always be suggested as a therapy-determining test. Full article

Radiolabeled somatostatin subtype 2 receptor (SST2R)-antagonists have shown advantageous profiles for cancer theranostics compared with agonists. On the other hand, the newly introduced hybrid chelator (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA^5m) rapidly binds Ga-68 (t_1/2: 67.7 min) at much lower temperature, thus allowing for quick access to “ready-for-injection” [⁶⁸Ga]Ga-tracers in hospitals. We herein introduce [⁶⁸Ga]Ga-DATA^5m-LM4 for PET/CT imaging of SST₂R-positive human tumors. LM4 was obtained by 4Pal³/Tyr³-substitution in the known SST₂R antagonist LM3 (H-DPhe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH₂) and DATA^5m was coupled at the N-terminus for labeling with radiogallium (Ga-67/68). [⁶⁷Ga]Ga-DATA^5m-LM4 was evaluated in HEK293-SST₂R cells and mice models in a head-to-head comparison with [⁶⁷Ga]Ga-DOTA-LM3. Clinical grade [⁶⁸Ga]Ga-DATA^5m-LM4 was prepared and injected in a neuroendocrine tumor (NET) patient for PET/CT imaging. DATA^5m-LM4 displayed high SST₂R binding affinity. [⁶⁷Ga]Ga-DATA^5m-LM4 showed markedly higher uptake in HEK293-SST₂R cells versus [⁶⁷Ga]Ga-DOTA-LM3 and was stable in vivo. In HEK293-SST₂R xenograft-bearing mice, it achieved longer tumor retention and less kidney uptake than [⁶⁷Ga]Ga-DOTA-LM3. [⁶⁸Ga]Ga-DATA^5m-LM4 accurately visualized tumor lesions with high contrast on PET/CT. In short, [⁶⁸Ga]Ga-DATA^5m-LM4 has shown excellent prospects for the PET/CT diagnosis of SST₂R-positive tumors, further highlighting the benefits of Ga-68 labeling in a hospital environment via the DATA^5m-chelator route. Full article

Sarcopenia is a multifactorial disease that limits autonomy for the growing elderly population. An optimal amount of dietary protein has shown to be important to maintain muscle mass during aging. Yet, the optimal distribution of that dietary protein has not been fully clarified. The aim of the present study was to examine whether an even, compared to a skewed, distribution of daily dietary protein leads to higher muscle protein synthesis and amino acid utilization. Twelve healthy males and twelve healthy females aged between 65 and 80 years were block randomized to either an even (EVEN, n = 12) or skewed (SKEWED, n = 12) dietary protein distribution for three daily main meals. Seven days of habituation were followed by three trial days, which were initiated by oral intake of deuterium oxide (D₂O). The dietary protein throughout all trial meals was intrinsically labelled with ²H₅-phenylalanine. Blood samples were drawn daily, and muscle biopsies were taken before and at the end of the trial to measure muscle protein synthesis (FSR) and muscle protein incorporation of the dietary-protein-derived tracer. Muscle protein FSR was no different between the two groups (EVEN 2.16 ± 0.13%/day and SKEWED 2.23 ± 0.09%/day, p = 0.647), and the muscle protein incorporation of the intrinsically labeled ²H₅-phenylalanine tracer was not different between the two groups (EVEN 0.0049 ± 0.0004 MPE% and SKEWED 0.0054 ± 0.0003 MPE%, p = 0.306). In conclusion, the daily distribution pattern of the dietary protein did not affect muscle protein synthesis or the utilization of dietary protein. Full article

Although the tracer (2S,4S)4–[¹⁸F]FPArg is expected to provide a powerful imaging method for the diagnosis and treatment of clinical tumors, it has not been realized due to the low yield of chemical synthesis and radiolabeling. A simple synthetic method for the radiolabeled precursor of (2S,4S)4–[¹⁸F]FPArg in stable yield was obtained by adjusting the sequence of the synthetic steps. Furthermore, the biodistribution experiments confirmed that (2S,4S)4–[¹⁸F]FPArg could be cleared out quickly in wild type mouse. Cell uptake experiments and U87MG tumor mouse microPET–CT imaging experiments showed that the tumor had high uptake of (2S,4S)4–[¹⁸F]FPArg and the clearance was slow, but (2S,4S)4–[¹⁸F]FPArg was rapidly cleared in normal brain tissue. MicroPET–CT imaging of nude mice bearing orthotopic HS683–Luc showed that (2S,4S)4–[¹⁸F]FPArg can penetrate blood–brain barrier and image gliomas with a high contrast. Therefore, (2S,4S)4–[¹⁸F]FPArg is expected to be further applied in the diagnosis and efficacy evaluation of clinical glioma. Full article

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians’ rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use. Full article