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.

B-Glycine as a marker for ß cell imaging and ß cell mass evaluation.

PURPOSE: ß cell mass (BCM) and function are essential to the diagnosis and therapy of diabetes. Diabetic patients serve ß cell loss is, and damage of ß cells leads to severe insulin deficiency. Our understanding of the role of BCM in diabetes progression is extremely limited by lacking efficient methods to evaluate BCM in vivo. In vitro methods of labeling islets, including loading of contrast reagent or integration of exogenous biomarker, require artificial manipulation on islets, of which the clinical application is limited. Imaging methods targeting endogenous biomarkers may solve the above problems. However, traditional reagents targeting GLP-1R and VAMT2 result in a high background of adjacent tissues, complicating the identification of pancreatic signals. Here, we report a non-invasive and quantitative imaging technique by using radiolabeled glycine mimics ([18F]FBG, a boron-trifluoride derivative of glycine) to assay islet function and monitor BCM changes in living animals. METHODS: Glycine derivatives, FBG, FBSa, 2Me-FBG, 3Me-FBG, were successfully synthesized and labeled with 18F. Specificity of glycine derivatives were characterized by in vitro experiment. PET imaging and biodistribution studies were performed in animal models carring GLYT over-expressed cells. In vivo evaluation of BCM with [18F]FBG were performed in STZ (streptozocin) induced T1D (type 1 diabetes) models. RESULTS: GLYT responds to excess blood glycine levels and transports glycine into islet cells to maintain the activity of the glycine receptor (GLYR). Best PET imaging condition was 80 min after given a total of 240 ~ 250 nmol imaging reagent (a mixture of [18F]FBG and natural glycine) intravenously. [18F]FBG can detect both endogenous and exogenous islets clearly in vivo. When applied to STZ induced T1D mouse models, total uptake of [18F]FBG in the pancreas exhibited a linear correlation with survival BCM. CONCLUSION: [18F]FBG targeting the endogenous glycine transporter (GLYT), which is highly expressed on islet cells, avoiding extra modification on islet cells. Meanwhile the highly restricted expression pattern of GLYT excluded the background in adjacent tissues. This [18F]FBG-based imaging technique provides a non-invasive method to quantify BCM in vivo, implying a new evaluation index for diabetic assessment.

Synthesis and Evaluation of 18F-Labeled Boramino Acids as Potential New Positron Emission Tomography Agents for Cancer Management.

Boron neutron capture therapy (BNCT) is a promising cancer treatment strategy that utilizes boron-containing ligands. In this report, a series of substituted boramino acids were synthesized and evaluated, aiming to obtain metabolically stable boron-derived agents that could integrate positron emission tomography (PET) with BNCT (a theranostic agent). Based on the phenylalanine (Phe) core structure, the impact of substitution groups on tumor accumulation was studied. The agents were labeled with fluorine-18 in 27.2-66.8% yield via the 18F-19F isotope exchange reaction. In B16-F10 tumor-bearing mice, [18F]-(R)-(1-ammonio-2-(4-methoxyphenyl) ethyl) trifluoroborate (R-[18F]-5a) demonstrated the best tumor uptake (5.54 ± 2.32% ID/g based on ex vivo biodistribution and 3.5 ± 0.04% ID/g based on PET imaging with the tumor-to-muscle ratio up to 2.6) and stability compared with other tested agents. Together, R-[18F]-5a is a promising agent that could potentially integrate PET and BNCT, whose treatment efficacy is worth further evaluation in the future.

18F-Boramino acid PET/CT in healthy volunteers and glioma patients.

PURPOSE: In this work, the safety, biodistribution, and radiation dosimetry of large neutral amino acid transporter type-1 (LAT-1) targeting PET tracer 18F-trifluorobborate-derived tyrosine (denoted as 18F-FBY) has been investigated. It is designed as a first-in-human study in healthy volunteers and to assay LAT-1 expression level in glioma patients. METHODS: Six healthy volunteers (3 M, 3 F) underwent whole-body PET acquisitions at multiple time points after bolus injection of 18F-FBY. Regions of interest (ROIs) were mapped manually on major organs, and then the time-activity curves (TACs) were obtained. Dosimetry was calculated with the OLINDA/EXM software. Thirteen patients who were suspected of glioma were scanned with PET/CT at 30 min after 18F-FBY injection. Within 7 days after PET/CT, the tumor was removed surgically, and LAT-1 immunohistochemical staining for LAT-1 was performed on tumor samples and correlated with 18F-FBY PET imaging. RESULTS: 18F-FBY was well tolerated by all healthy volunteers, and no adverse symptoms were observed or reported. 18F-FBY is rapidly cleared from the blood circulation and excreted mainly through the kidneys and urinary tract. The effective dose (ED) was 0.0039 ± 0.0006 mSv/MBq. In 14 surgical confirmed gliomas (one of the patiens had two gliomas), 18F-FBY uptake increased consistently with tumor grade, with maximum standard uptake values (SUVmax) of 0.28 ± 0.14 and 2.84 ± 0.46 and tumor-to-normal contralateral activity (T/N) ratio of 2.30 ± 1.26 and 24.56 ± 6.32 in low- and high-grade tumors, respectively. In addition to the significant difference in the uptakes between low- and high-grade gliomas (P < 0.001), the immunohistochemical staining confirmed the positive correlations between the SUVmax, LAT-1 expression (r2 = 0.80, P < 0.001), and Ki-67 labeling index (r2 = 0.79, P < 0.001). CONCLUSION: 18F-FBY is a PET tracer with favorable dosimetry profile and pharmacokinetics. It has the potential to assay LAT-1 expression in glioma patients and may provide imaging guidance for further boron neutron capture therapy of gliomas. TRIAL REGISTRATION: clinicaltrials.gov (NCT03980431).

Side Chain Optimization Remarkably Enhances the in Vivo Stability of 18F-Labeled Glutamine for Tumor Imaging.

Similar to glycolysis, glutaminolysis acts as a vital energy source in tumor cells, providing building blocks for the metabolic needs of tumor cells. To capture glutaminolysis in tumors, 18F-(2S,4R)4-fluoroglutamine ([18F]FGln) and 18F-fluoroboronoglutamine ([18F]FBQ) have been successfully developed for positron emission tomography (PET) imaging, but these two molecules lack stability, resulting in undesired yet significant bone uptake. In this study, we found that [18F]FBQ-C2 is a stable Gln PET tracer by adding two more methylene groups to the side chain of [18F]FBQ. [18F]FBQ-C2 was synthesized with a good radiochemical yield of 35% and over 98% radiochemical purity. [18F]FBQ-C2 showed extreme stability in vitro, and no defluorination was observed after 2 h in phosphate buffered saline at 37 °C. The competitive inhibition assay results indicated that [18F]FBQ-C2 enters cells via the system ASC and N, similar to natural glutamine, and can be transported by tumor-overexpressed ASCT2. PET imaging and biodistribution results indicated that [18F]FBQ-C2 is stable in vivo with low bone uptake (0.81 ± 0.20% ID/g) and can be cleared rapidly from most tissues. Dynamic scan and pharmacokinetic studies using BGC823-xenograft-bearing mice revealed that [18F]FBQ-C2 accumulates specifically in tumors, with a longer half-life (101.18 ± 6.50 min) in tumor tissues than in other tissues (52.70 ± 12.44 min in muscle). Biodistribution exhibits a high tumor-to-normal tissue ratio (4.8 ± 1.7 for the muscle, 2.5 ± 1.0 for the stomach, 2.2 ± 0.9 for the liver, and 17.8 ± 8.4 for the brain). In conclusion, [18F]FBQ-C2 can be used to perform high-contrast Gln imaging of tumors and can serve as a PET tracer for clinical research.

One-step synthesis of an 18F-labeled boron-derived methionine analog: a substitute for 11C-methionine?

Amino acid-based tracers have been extensively investigated for positron emission tomography (PET) imaging of brain tumors, and 11C-methionine (11C-MET) is one of the most extensively investigated. However, widespread clinical use of 11C-MET is challenging due to the short half-life of 11C and low radiolabeling yield. In this issue of the European Journal of Nuclear Medicine and Molecular Imaging, Yang and colleagues report an 18F-labeled boron-derived methionine analog, 18F-B-MET, as a potential substitute for 11C-MET in PET imaging of glioma. The push-button synthesis, highly efficient radiolabeling, and good imaging performance in glioma models make this tracer a promising candidate for future clinical translation.

18F-Alanine Derivative Serves as an ASCT2 Marker for Cancer Imaging.

Amino acids derivative are well established molecular probes for diagnosis of a variety of cancer using positron emission tomography (PET). Recently, boramino acid (BAAs) was found as a prospective molecular platform for developing PET tracer. The objective of this study was to develop a 18F-labeled alanine derivative through displacing its carboxylate by trifluoroborate as a selective ASCT2 marker for cancer imaging. 18F-Ala-BF3 was first evaluated in healthy FVB/N mice in vivo, exhibiting rapid renal clearance with almost negligible uptake in stomach (1.53 ± 0.31%ID/g). Notable uptake was observed in thyroid (3.71 ± 0.49%ID/g, 40 min post injection), of which the uptake was significantly inhibited by co-injection with natural L-alanine. In addition, we further established 18F-Ala-BF3 on a human gastric cancer cell (BGC-823) xenografts bearing mouse model. Dynamic PET-CT scan revealed the optimal time window for tumor imaging, it was between 40 and 60 min post injection, when the BGC-823 xenografts uptake was 5.49 ± 1.47%ID/g ( n = 4), and the tumor-to-stomach, tumor-to-blood, tumor-to-muscle, and tumor-to-brain ratios were 3.27 ± 1.53, 3.80 ± 1.48, 3.47 ± 1.48, and 6.20 ± 1.47, respectively.

Synthesis and evaluation of an 18F-labeled boramino acid analog of aminosuberic acid for PET imaging of the antiporter system xC.

In this study, we synthesized 18F-ASu-BF3, a close boramino acid analog of 5-[18F]fluoro-aminosuberic acid (18F-ASu), via 18F-19F isotope exchange reaction and evaluated its potential for imaging with positron emission tomography (PET). 18F-ASu-BF3 was stable in mouse plasma and taken up into PC3 prostate cancer cells via the system xC- amino acid transporter. The continuous use of isoflurane for anesthesia during dynamic imaging acquisition slowed down the excretion of 18F-ASu-BF3 and enabled visualization of PC3 tumor xenografts in mice. In contrast, no tumor visualization was observed from static images of 18F-BF3-ASu due to its rapid renal excretion mediated in part by the organic anion transporter. Our data indicate that the pharmacokinetics of amino acids could be altered after being converted into their boramino acid analogs. Therefore, care should be taken when using the boramino acid strategy to design and prepare 18F-labeled tracers for imaging amino acid transporters/receptors with PET.

Preclinical study of an 18F-labeled glutamine derivative for cancer imaging.

INTRODUCTION: The emerging evidence that demonstrated the extra-demand of glutamine for cancer surviving strongly called for the development of PET tracer for imaging glutamine uptake in cancer. In this work, [18F]Gln-BF3 as a natural glutamine derivative was synthesized to explore its potential application of imaging glutamine uptake for cancer diagnosis. METHODS: [18F]Gln-BF3 was prepared by deprotection of purified precursor trityl-Gln-BF3 (amide bond protected with triphenylmethyl group) using TFA and radiolabeled using 18F-19F isotope exchange protocol. PET imaging and biodistribution studies were conducted in Balb/c mice bearing 4T1 xenograft. RESULTS: Gln-BF3 was identified with HRMS ([M-H]- = 169.0765). [18F]Gln-BF3 was radiolabeled in high radiochemical yield (RCY > 25%) and characterized with Radio-HPLC-MS. Preliminary PET imaging showed the radioactivity was fast cleared from muscle tissue and excreted mainly via the renal pathway. PET study demonstrated that uptake of [18F]Gln-BF3 in 4T1 xenografts was significant. The biodistribution results of [18F]Gln-BF3 in mice bearing 4T1 xenograft indicate a tumor-to-muscle ratio of 2.58 ±â€¯0.64 (n = 4) and a 6.29 ±â€¯0.42%ID/g (n = 4) uptake in tumor at 45 min post injection. CONCLUSION: [18F]Gln-BF3 was radiolabeled in a "kit-like" manner and showed notable and tumor-selective uptake in tumor-bearing animal models, suggesting that this new strategy of radiolabeling amino acid provided a promising solution for the future development of glutamine-derived PET tracers.