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1.
Nat Commun ; 15(1): 5109, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38877019

ABSTRACT

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.


Subject(s)
Alzheimer Disease , Brain , Fluorine Radioisotopes , Positron-Emission Tomography , Radiopharmaceuticals , Tauopathies , tau Proteins , Positron-Emission Tomography/methods , Animals , Humans , Tauopathies/diagnostic imaging , Tauopathies/metabolism , Brain/diagnostic imaging , Brain/metabolism , Ligands , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Rats , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Fluorine Radioisotopes/chemistry , tau Proteins/metabolism , Male
2.
Org Biomol Chem ; 22(22): 4550-4558, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38768281

ABSTRACT

Nuclear imaging of aggregated α-synuclein pathology is an urgent clinical need for Parkinson's disease, yet promising tracers for brain α-synuclein aggregates are still rare. In this work, a class of compact benzothiazole derivatives was synthesized and evaluated for α-synuclein aggregates. Among them, azobenzothiazoles exhibited specific and selective detection of α-synuclein aggregates under physiological conditions. Fluoro-pegylated azobenzothiazole NN-F further demonstrated high-affinity binding to α-synuclein aggregates and efficient 18F-radiolabeling via nucleophilic displacement of a tosyl precursor. [18F]NN-F was stable in plasma in vitro and showed efficient brain uptake with little defluorination in vivo.


Subject(s)
Benzothiazoles , Brain , Fluorine Radioisotopes , Protein Aggregates , alpha-Synuclein , alpha-Synuclein/metabolism , alpha-Synuclein/chemistry , Fluorine Radioisotopes/chemistry , Benzothiazoles/chemistry , Benzothiazoles/chemical synthesis , Brain/metabolism , Brain/diagnostic imaging , Animals , Humans , Mice , Molecular Structure , Positron-Emission Tomography
3.
J Phys Chem B ; 128(22): 5454-5462, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38807468

ABSTRACT

The compound 2-{[(trifluoromethyl)sulfonyl]oxy}propane-1,3-diyl bis(4-methylbenzenesulfonate) (TPB) is a crucial intermediate in the synthesis of 18F-radiolabeled cromolyn derivatives. In this work, we combine 1H NMR spectroscopy, X-ray crystallography, ab initio molecular dynamics, and NMR calculations to examine the structure, interactions, and solvation dynamics of the TPB molecule. In CDCl3, the CH2 groups within its glyceryl-derived linker exhibit a single set of proton signals in the 1H NMR measurements. However, when TPB is dissolved in DMSO-d6, distinct splitting patterns emerge despite its seemingly symmetric chemical structure. Crystallographic analysis further unveils the absence of overall symmetry in its three-dimensional arrangement. To elucidate these unique NMR features, we carry out ab initio molecular dynamics simulations and characterize the solvation structures and dynamics of TPB in CHCl3 and DMSO solutions. In contrast to the predominantly nonpolar nature of the CHCl3 solvents, DMSO directly participates in C-H···O hydrogen-bonding interactions with the solute molecule, leading to the splitting of its -CH2 chemical shifts into two distinct distributions. The comprehensive understanding of the structure and solvation interactions of TPB provides essential insights into its application in the radiofluorination reactions of cromolyn derivatives and holds promise for the future development of radiolabeled dimeric drugs.


Subject(s)
Fluorine Radioisotopes , Hydrogen Bonding , Molecular Dynamics Simulation , Fluorine Radioisotopes/chemistry , Proton Magnetic Resonance Spectroscopy , Crystallography, X-Ray , Dimerization , Isotope Labeling , Density Functional Theory , Molecular Structure
4.
Mol Pharm ; 21(6): 2795-2812, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38747353

ABSTRACT

O-([18F]Fluoroethyl)-l-tyrosine ([18F]FET) is actively transported into the brain and cancer cells by LAT1 and possibly other amino acid transporters, which enables brain tumor imaging by positron emission tomography (PET). However, tumor delivery of this probe in the presence of competing amino acids may be limited by a relatively low affinity for LAT1. The aim of the present work was to evaluate the meta-substituted [18F]FET analog m-[18F]FET and the methyl ester [18F]FET-OMe, which were designed to improve tumor delivery by altering the physicochemical, pharmacokinetic, and/or transport properties. Both tracers could be prepared with good radiochemical yields of 41-56% within 66-90 min. Preclinical evaluation with [18F]FET as a reference tracer demonstrated reduced in vitro uptake of [18F]FET-OMe by U87 glioblastoma cells and no advantage for in vivo tumor imaging. In contrast, m-[18F]FET showed significantly improved in vitro uptake and accelerated in vivo tumor accumulation in an orthotopic glioblastoma model. As such, our work identifies m-[18F]FET as a promising alternative to [18F]FET for brain tumor imaging that deserves further evaluation with regard to its transport properties and in vivo biodistribution.


Subject(s)
Brain Neoplasms , Positron-Emission Tomography , Radiopharmaceuticals , Tyrosine , Animals , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/metabolism , Humans , Mice , Tyrosine/analogs & derivatives , Tyrosine/chemistry , Cell Line, Tumor , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Tissue Distribution , Fluorine Radioisotopes/chemistry , Glioblastoma/diagnostic imaging , Glioblastoma/metabolism , Mice, Nude , Large Neutral Amino Acid-Transporter 1/metabolism , Brain/diagnostic imaging , Brain/metabolism
5.
Bioorg Med Chem ; 106: 117753, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38749342

ABSTRACT

The expression of prostate-specific membrane antigen (PSMA) in prostate cancer is 100-1000 times higher than that in normal tissues, and it has shown great advantages in the diagnosis and treatment of prostate cancer. The combination of PSMA and PET imaging technology based on the principle of metabolic imaging can achieve high sensitivity and high specificity for diagnosis. Due to its suitable half-life (109 min) and good positron abundance (97%), as well as its cyclotron accelerated generation, 18F has the potential to be commercialize, which has attracted much attention. In this article, we synthesized a series of fluorosulfate PET tracers targeting PSMA. All four analogues have shown high affinity to PSMA (IC50 = 1.85-5.15 nM). After the radioisotope exchange labeling, [18F]L9 and [18F]L10 have PSMA specific cellular uptake (0.65 ± 0.04% AD and 1.19 ± 0.03% AD) and effectively accumulated in 22Rv1 xenograft mice model. This study demonstrates that PSMA-1007-based PSMA-targeted aryl [18F]fluorosulfate novel tracers have the potential for PET imaging in tumor tissues.


Subject(s)
Antigens, Surface , Drug Design , Fluorine Radioisotopes , Positron-Emission Tomography , Radiopharmaceuticals , Animals , Humans , Male , Fluorine Radioisotopes/chemistry , Mice , Antigens, Surface/metabolism , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/metabolism , Glutamate Carboxypeptidase II/metabolism , Molecular Structure , Cell Line, Tumor , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/metabolism , Structure-Activity Relationship
6.
ACS Sens ; 9(5): 2605-2613, 2024 05 24.
Article in English | MEDLINE | ID: mdl-38718161

ABSTRACT

Several new lines of research have demonstrated that a significant number of amyloid-ß peptides found in Alzheimer's disease (AD) are truncated and undergo post-translational modification by glutaminyl cyclase (QC) at the N-terminal. Notably, QC's products of Abeta-pE3 and Abeta-pE11 have been active targets for investigational drug development. This work describes the design, synthesis, characterization, and in vivo validation of a novel PET radioligand, [18F]PB0822, for targeted imaging of QC. We report herein a simplified and robust chemistry for the synthesis of the standard compound, [19F]PB0822, and the corresponding [18F]PB0822 radioligand. The PET probe was developed with 99.9% radiochemical purity, a molar activity of 965 Ci.mmol-1, and an IC50 of 56.3 nM, comparable to those of the parent PQ912 inhibitor (62.5 nM). Noninvasive PET imaging showed that the probe is distributed in the brain 5 min after intravenous injection. Further, in vivo PET imaging with [18F]PB0822 revealed that AD 5XFAD mice harbor significantly higher QC activity than WT counterparts. The data also suggested that QC activity is found across different brain regions of the tested animals.


Subject(s)
Alzheimer Disease , Aminoacyltransferases , Positron-Emission Tomography , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Positron-Emission Tomography/methods , Aminoacyltransferases/metabolism , Aminoacyltransferases/antagonists & inhibitors , Animals , Mice , Fluorine Radioisotopes/chemistry , Brain/diagnostic imaging , Brain/metabolism , Brain/enzymology , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Biomarkers/metabolism , Humans , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/analysis , Ligands
7.
Org Lett ; 26(20): 4308-4313, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38728659

ABSTRACT

In this study, we introduce a practical methodology for the synthesis of PET probes by seamlessly combining flow chemistry with photoredox radiofluorination. The clinical PET tracer 6-[18F]FDOPA was smoothly prepared in a 24.3% non-decay-corrected yield with over 99.0% radiochemical purity (RCP) and enantiomeric excess (ee), notably by a simple cartridge-based purification. The flow chemistry-enhanced photolabeling method supplies an efficient and versatile solution for the synthesis of 6-[18F]FDOPA and for more PET tracer development.


Subject(s)
Fluorine Radioisotopes , Positron-Emission Tomography , Fluorine Radioisotopes/chemistry , Molecular Structure , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Oxidation-Reduction , Dihydroxyphenylalanine/chemistry , Dihydroxyphenylalanine/chemical synthesis , Dihydroxyphenylalanine/analogs & derivatives , Photochemical Processes , Halogenation
8.
Inorg Chem ; 63(21): 9831-9841, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38739498

ABSTRACT

Aluminum fluoride (AlF) complexes have been used over the past decade to incorporate [18F]fluoride into large biomolecules in a highly selective fashion by using relatively facile conditions. However, despite their widespread usage, there are a large number of variations in the reaction conditions, without a definitive discussion provided on the mechanism to understand how these changes would alter the end result. Herein, we report a detailed mechanistic investigation of the reaction, using a mixture of theoretical studies, fluorine-19 and fluorine-18 chemistry, and the consequences it has on the efficient clinical translation of AlF-containing imaging agents.


Subject(s)
Aluminum Compounds , Chelating Agents , Fluorides , Fluorides/chemistry , Aluminum Compounds/chemistry , Chelating Agents/chemistry , Chelating Agents/chemical synthesis , Fluorine Radioisotopes/chemistry , Molecular Structure
9.
J Med Chem ; 67(10): 8361-8371, 2024 May 23.
Article in English | MEDLINE | ID: mdl-38726551

ABSTRACT

Due to the complex heterogeneity in different cancer types, the heterodimeric strategy has been intensively practiced to improve the effectiveness of tumor diagnostics. In this study, we developed a series of novel 18F-labeled biotin/FAPI-conjugated heterobivalent radioligands ([18F]AlF-NSFB, [18F]AlF-NSFBP2, and [18F]AlF-NSFBP4), synergistically targeting both fibroblast activation protein (FAP) and biotin receptor (BR), to enhance specific tumor uptake and retention. The in vitro and in vivo biological properties of these dual-targeting tracers were evaluated, with a particular focus on positron emission tomography imaging in A549 and HT1080-FAP tumor-bearing mice. Notably, in comparison to the corresponding FAP-targeted monomer [18F]AlF-NSF, biotin/FAPI-conjugated heterodimers exhibited a high uptake in tumor and prolong retention. In conclusion, as a proof-of-concept study, the findings validated the superiority of biotin/FAPI-conjugated heterodimers and the positive influence of biotin and linker on pharmacokinetics of radioligands. Within them, the bispecific [18F]AlF-NSFBP4 holds significant promise as a candidate for further clinical translational studies.


Subject(s)
Biotin , Fluorine Radioisotopes , Animals , Humans , Fluorine Radioisotopes/chemistry , Biotin/chemistry , Biotin/pharmacokinetics , Mice , Drug Design , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacology , Positron-Emission Tomography , Mice, Nude , Tissue Distribution , Dimerization , Cell Line, Tumor , Mice, Inbred BALB C
10.
Bioorg Chem ; 147: 107352, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38640719

ABSTRACT

Glypican-3 (GPC3) is markedly overexpressed in hepatocellular carcinoma (HCC) and not expressed in normal liver tissues. In this study, a novel peptide PET imaging agent ([18F]AlF-NOTA-IPB-GPC3P) was developed to target GPC3 expressed in tumors. The overall radiochemical yield of [18F]AlF-NOTA-IPB-GPC3P was 10-15 %, and its lipophilicity, expressed as the logD value at a pH of 7.4, was -1.18 ± 0.06 (n = 3). Compared to the previously reported tracer [18F]AlF-GP2633, [18F]AlF-NOTA-IPB-GPC3P exhibited higher cellular uptake (15.13 vs 5.96) and internalized rate (80.63 % vs 35.93 %) in Huh7 cells at 120 min. Micro-PET/CT and biodistribution studies further demonstrated that [18F]AlF-NOTA-IPB-GPC3P exhibited significantly increased tumor uptake and prolonged tumor residence in Huh7 tumors compared to [18F]AlF-GP2633 (4.66 ± 0.22 % ID/g vs 0.72 ± 0.09 % ID/g at 60 min, p < 0.001; 5.05 ± 0.23 % ID/g vs 0.35 ± 0.08 % ID/g at 120 min, p < 0.001, respectively). Furthermore, the tumor-to-organ ratios of [18F]AlF-NOTA-IPB-GPC3P surpassed those of [18F]AlF-GP2633. Our results support the utilization of [18F]AlF-NOTA-IPB-GPC3P as a PET imaging agent targeting the GPC3 receptor for tumor detection.


Subject(s)
Fluorine Radioisotopes , Glypicans , Positron-Emission Tomography , Animals , Humans , Mice , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Fluorine Radioisotopes/chemistry , Glypicans/metabolism , Heterocyclic Compounds, 1-Ring , Liver Neoplasms/diagnostic imaging , Mice, Nude , Molecular Structure , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Structure-Activity Relationship , Tissue Distribution
11.
Angew Chem Int Ed Engl ; 63(26): e202404945, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38624193

ABSTRACT

Herein, we disclose that pyridinium salts derived from abundant (hetero)anilines represent a novel precursor class for nucleophilic aromatic substitution reactions with [18F]fluoride. The value of this new 18F-fluorodeamination is demonstrated with the synthesis of over 30 structurally diverse and complex heteroaryl 18F-fluorides, several derived from scaffolds that were yet to be labelled with fluorine-18. The protocol tolerates heteroarenes and functionalities commonly found in drug discovery libraries, and is amenable to scale-up and automation on a commercial radiosynthesiser.


Subject(s)
Aniline Compounds , Fluorine Radioisotopes , Pyridinium Compounds , Salts , Aniline Compounds/chemistry , Pyridinium Compounds/chemistry , Pyridinium Compounds/chemical synthesis , Salts/chemistry , Fluorine Radioisotopes/chemistry , Halogenation , Molecular Structure
12.
J Med Chem ; 67(8): 6207-6217, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38607332

ABSTRACT

Sigma-1 receptor (σ1R) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain σ1R could provide a powerful tool for better understanding the underlying pathomechanism of σ1R in AD. In this study, we successfully developed a 18F-labeled σ1R radiotracer [18F]CNY-05 via an innovative ruthenium (Ru)-mediated 18F-deoxyfluorination method. [18F]CNY-05 exhibited preferable brain uptake, high specific binding, and slightly reversible pharmacokinetics within the PET scanning time window. PET imaging of [18F]CNY-05 in nonhuman primates (NHP) indicated brain permeability, metabolic stability, and safety. Moreover, autoradiography and PET studies of [18F]CNY-05 in the AD mouse model found a significantly decreased brain uptake compared to that in wild-type mice. Collectively, we have provided a novel 18F-radiolabeled σ1R PET probe, which enables visualizing brain σ1R in health and neurological diseases.


Subject(s)
Alzheimer Disease , Brain , Fluorine Radioisotopes , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, sigma , Sigma-1 Receptor , Receptors, sigma/metabolism , Animals , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Brain/metabolism , Brain/diagnostic imaging , Fluorine Radioisotopes/chemistry , Positron-Emission Tomography/methods , Mice , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Male , Molecular Imaging/methods , Halogenation , Tissue Distribution , Humans
13.
J Med Chem ; 67(8): 6327-6343, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38570909

ABSTRACT

The interleukin-8 receptor beta (CXCR2) is a highly promising target for molecular imaging of inflammation and inflammatory diseases. This is due to its almost exclusive expression on neutrophils. Modified fluorinated ligands were designed based on a squaramide template, with different modification sites and synthetic strategies explored. Promising candidates were then tested for affinity to CXCR2 in a NanoBRET competition assay, resulting in tracer candidate 16b. As direct 18F-labeling using established tosyl chemistry did not yield the expected radiotracer, an indirect labeling approach was developed. The radiotracer [18F]16b was obtained with a radiochemical yield of 15% using tert-butyl (S)-3-(tosyloxy)pyrrolidine carboxylate and a pentafluorophenol ester. The subsequent time-dependent uptake of [18F]16b in CXCR2-negative and CXCR2-overexpressing human embryonic kidney cells confirmed the radiotracer's specificity. Further studies with human neutrophils revealed its diagnostic potential for functional imaging of neutrophils.


Subject(s)
Fluorine Radioisotopes , Neutrophils , Positron-Emission Tomography , Radiopharmaceuticals , Receptors, Interleukin-8B , Receptors, Interleukin-8B/metabolism , Humans , Fluorine Radioisotopes/chemistry , Neutrophils/metabolism , Positron-Emission Tomography/methods , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , HEK293 Cells
14.
Bioorg Med Chem Lett ; 105: 129744, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38614152

ABSTRACT

Two tryptophan compound classes 5- and 6-borono PEGylated boronotryptophan derivatives have been prepared for assessing their aqueous solubility as formulation of injections for boron neutron capture therapy (BNCT). The PEGylation has improved their aqueous solubility thereby increasing their test concentration in 1 mM without suffering from toxicity. In-vitro uptake assay of PEGylated 5- and 6-boronotryptophan showed that the B-10 concentration can reach 15-50 ppm in U87 cell whereas the uptake in LN229 cell varies. Shorter PEG compound 6-boronotryptophanPEG200[18F] was obtained in 1.7 % radiochemical yield and the PET-derived radioradioactivity percentage in 18 % was taken up by U87 tumor at the limb of xenograft mouse. As high as tumor to normal uptake ratio in 170 (T/N) was obtained while an inferior radioactivity uptake of 3 % and T/N of 8 was observed in LN229 xenografted mouse.


Subject(s)
Boron Neutron Capture Therapy , Brain Neoplasms , Fluorine Radioisotopes , Polyethylene Glycols , Positron-Emission Tomography , Animals , Mice , Humans , Fluorine Radioisotopes/chemistry , Polyethylene Glycols/chemistry , Cell Line, Tumor , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/radiotherapy , Brain Neoplasms/metabolism , Boron Compounds/chemistry , Boron Compounds/pharmacokinetics , Boron Compounds/chemical synthesis , Tryptophan/chemistry , Tryptophan/analogs & derivatives , Tryptophan/pharmacokinetics , Tryptophan/chemical synthesis , Molecular Structure
15.
Bioconjug Chem ; 35(5): 665-673, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38598424

ABSTRACT

Enhancing the accumulation and retention of small-molecule probes in tumors is an important way to achieve accurate cancer diagnosis and therapy. Enzyme-stimulated macrocyclization of small molecules possesses great potential for enhanced positron emission tomography (PET) imaging of tumors. Herein, we reported an 18F-labeled radiotracer [18F]AlF-RSM for legumain detection in vivo. The tracer was prepared by a one-step aluminum-fluoride-restrained complexing agent ([18F]AlF-RESCA) method with high radiochemical yield (RCY) (88.35 ± 3.93%) and radiochemical purity (RCP) (>95%). More notably, the tracer can be transformed into a hydrophobic macrocyclic molecule under the joint action of legumain and reductant. Simultaneously, the tracer could target legumain-positive tumors and enhance accumulation and retention in tumors, resulting in the amplification of PET imaging signals. The enhancement of radioactivity enables PET imaging of legumain activity with high specificity. We envision that, by combining this highly efficient 18F-labeled strategy with our intramolecular macrocyclization reaction, a range of radiofluorinated tracers can be designed for tumor PET imaging and early cancer diagnosis in the future.


Subject(s)
Cysteine Endopeptidases , Fluorine Radioisotopes , Positron-Emission Tomography , Positron-Emission Tomography/methods , Fluorine Radioisotopes/chemistry , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/analysis , Animals , Cyclization , Mice , Humans , Radiopharmaceuticals/chemistry , Cell Line, Tumor , Mice, Inbred BALB C , Fluorides/chemistry , Mice, Nude
16.
Eur J Med Chem ; 271: 116380, 2024 May 05.
Article in English | MEDLINE | ID: mdl-38615410

ABSTRACT

Imaging of the A1 adenosine receptor (A1R) by positron emission tomography (PET) with 8-cyclopentyl-3-(3-[18F]fluoropropyl)-1-propyl-xanthine ([18F]CPFPX) has been widely used in preclinical and clinical studies. However, this radioligand suffers from rapid peripheral metabolism and subsequent accumulation of radiometabolites in the vascular compartment. In the present work, we prepared four derivatives of CPFPX by replacement of the cyclopentyl group with norbornane moieties. These derivatives were evaluated by competition binding studies, microsomal stability assays and LC-MS analysis of microsomal metabolites. In addition, the 18F-labeled isotopologue of 8-(1-norbornyl)-3-(3-fluoropropyl)-1-propylxanthine (1-NBX) as the most promising candidate was prepared by radiofluorination of the corresponding tosylate precursor and the resulting radioligand ([18F]1-NBX) was evaluated by permeability assays with Caco-2 cells and in vitro autoradiography in rat brain slices. Our results demonstrate that 1-NBX exhibits significantly improved A1R affinity and selectivity when compared to CPFPX and that it does not give rise to lipophilic metabolites expected to cross the blood-brain-barrier in microsomal assays. Furthermore, [18F]1-NBX showed a high passive permeability (Pc = 6.9 ± 2.9 × 10-5 cm/s) and in vitro autoradiography with this radioligand resulted in a distribution pattern matching A1R expression in the brain. Moreover, a low degree of non-specific binding (5%) was observed. Taken together, these findings identify [18F]1-NBX as a promising candidate for further preclinical evaluation as potential PET tracer for A1R imaging.


Subject(s)
Positron-Emission Tomography , Receptor, Adenosine A1 , Xanthines , Receptor, Adenosine A1/metabolism , Humans , Animals , Xanthines/chemistry , Xanthines/chemical synthesis , Rats , Caco-2 Cells , Male , Molecular Structure , Structure-Activity Relationship , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/chemical synthesis , Dose-Response Relationship, Drug , Fluorine Radioisotopes/chemistry
17.
Bioconjug Chem ; 35(5): 567-574, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38634516

ABSTRACT

The exploration of pharmaceutically active agents and positron emission tomography (PET) tracers targeting CXCR4 has been a focal point in cancer research given its pivotal role in the development and progression of various cancers. While significant strides have been made in PET imaging with radiometal-labeled tracers, the landscape of 18F-labeled small molecule tracers remains relatively limited. Herein, we introduce a novel and promising derivative, [18F]SFB-AMD3465, as a targeted PET tracer for CXCR4. The compound was synthesized by modifying the pyridine ring of AMD3465, which was subsequently labeled with 18F using [18F]SFB. The study provides comprehensive insights into the design, synthesis, and biological evaluation of [18F]SFB-AMD3465. In vitro and in vivo assessments demonstrated the CXCR4-dependent, specific, and sensitive uptake of [18F]SFB-AMD3465 in the CXCR4-overexpressing 4T1 cell line and the corresponding xenograft-bearing mouse model. These findings contribute to bridging the gap in 18F-labeled PET tracers for CXCR4 and underscore the potential of [18F]SFB-AMD3465 as a PET radiotracer for in vivo CXCR4 imaging.


Subject(s)
Fluorine Radioisotopes , Positron-Emission Tomography , Receptors, CXCR4 , Animals , Receptors, CXCR4/analysis , Receptors, CXCR4/metabolism , Positron-Emission Tomography/methods , Mice , Fluorine Radioisotopes/chemistry , Female , Cell Line, Tumor , Humans , Pyridines/chemistry , Pyridines/pharmacokinetics , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution
18.
J Med Chem ; 67(9): 7068-7087, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38656144

ABSTRACT

Fibroblast activation protein (FAP) is a very reliable biomarker for tissue remodeling. FAP has so far mainly been studied in oncology, but there is growing interest in the enzyme in other diseases like fibrosis. Recently, FAP-targeting diagnostics and therapeutics have emerged, of which the so-called FAPIs are among the most promising representatives. FAPIs typically have a relatively high molecular weight and contain very polar, multicharged chelator moieties. While this is not limiting the application of FAPIs in oncology, more druglike FAPIs could be required to optimally study diseases characterized by denser, less permeable tissue. In response, we designed the first druglike 18F-labeled FAPIs. We report target potencies, biodistribution, and pharmacokinetics and demonstrate FAP-dependent uptake in murine tumor xenografts. Finally, this paper puts forward compound 10 as a highly promising, druglike FAPI for 18F-PET imaging. This molecule is fit for additional studies in fibrosis and its preclinical profile warrants clinical investigation.


Subject(s)
Endopeptidases , Fluorine Radioisotopes , Gelatinases , Membrane Proteins , Positron-Emission Tomography , Serine Endopeptidases , Animals , Positron-Emission Tomography/methods , Endopeptidases/metabolism , Fluorine Radioisotopes/chemistry , Gelatinases/metabolism , Gelatinases/antagonists & inhibitors , Membrane Proteins/metabolism , Membrane Proteins/antagonists & inhibitors , Humans , Mice , Tissue Distribution , Serine Endopeptidases/metabolism , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacology , Cell Line, Tumor , Female
19.
Eur J Nucl Med Mol Imaging ; 51(8): 2444-2457, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38480552

ABSTRACT

PURPOSE: The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients. METHODS: Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with 18F by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient-derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [18F]RCCB6). RESULTS: We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [18F]RCCB3 and [18F]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [18F]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [18F]RCCB6. In a pilot translational study, [18F]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than 18F-FDG PET/CT in a patient with ccRCC. CONCLUSION: The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [18F]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [18F]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Positron Emission Tomography Computed Tomography , Humans , Carcinoma, Renal Cell/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Kidney Neoplasms/diagnostic imaging , Female , Male , Fluorine Radioisotopes/chemistry , Animals , Mice , Middle Aged , Single-Domain Antibodies , Aged , Cell Line, Tumor , Tissue Distribution
20.
Mol Pharm ; 21(4): 2034-2042, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38456403

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis and nonspecific symptoms and progresses rapidly, is the most common pancreatic cancer type. Inhibitors targeting KRAS G12D and G12C mutations have been pivotal in PDAC treatment. Cancer cells with different KRAS mutations exhibit various degrees of glutamine dependency; in particular, cells with KRAS G12D mutations exhibit increased glutamine uptake. (2S,4R)-4-[18F]FGln has recently been developed for clinical cancer diagnosis and tumor cell metabolism analysis. Thus, we verified the heterogeneity of glutamine dependency in PDAC models with different KRAS mutations by a visual and noninvasive method with (2S,4R)-4-[18F]FGln. Two tumor-bearing mouse models (bearing the KRAS G12D or G12C mutation) were injected with (2S,4R)-4-[18F]FGln, and positron emission tomography (PET) imaging features and biodistribution were observed and analyzed. The SUVmax in the regions of interest (ROI) was significantly higher in PANC-1 (G12D) tumors than in MIA PaCa-2 (G12C) tumors. Biodistribution analysis revealed higher tumor accumulation of (2S,4R)-4-[18F]FGln and other metrics, such as T/M and T/B, in the PANC-1 mouse models compared to those in the MIAPaCa-2 mouse models. In conclusion, PDAC cells with the KRAS G12D and G12C mutations exhibit various degrees of (2S,4R)-4-[18F]FGln uptake, indicating that (2S,4R)-4-[18F]FGln might be applied to detect KRAS G12C and G12D mutations and provide treatment guidance.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Animals , Mice , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Pancreatic Ductal/genetics , Glutamine/metabolism , Glutamine/pharmacology , Mutation , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Tissue Distribution , Fluorine Radioisotopes/chemistry , Fluorine Radioisotopes/pharmacology
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