Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule ¹⁸F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, 12 and 13, were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC₅₀ 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [¹⁸F]fluoride exchange ([¹⁸F]SuFEx) reaction to furnish [¹⁸F]12 and [¹⁸F]13 in high activity yields (AY) of 39–56% and molar activities (A_m) between 20–55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and ¹⁸F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either ¹⁸F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [¹⁸F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development.

Purpose: The preclinical evaluation of 3-l- and 3-d-[¹⁸F]FPhe in comparison to [¹⁸F]FET, an established tracer for tumor imaging. Methods: In vitro studies were conducted with MCF-7, PC-3, and U87 MG human tumor cell lines. In vivo µPET studies were conducted in healthy rats with/without the inhibition of peripheral aromatic l-amino acid decarboxylase by benserazide pretreatment (n = 3 each), in mice bearing subcutaneous MCF-7 or PC-3 tumor xenografts (n = 10), and in rats bearing orthotopic U87 MG tumor xenografts (n = 14). Tracer accumulation was quantified by SUV_max, SUV_mean and tumor-to-brain ratios (TBrR). Results: The uptake of 3-l-[¹⁸F]FPhe in MCF-7 and PC-3 cells was significantly higher relative to [¹⁸F]FET. The uptake of all three tracers was significantly reduced by the suppression of amino acid transport systems L or ASC. 3-l-[¹⁸F]FPhe but not 3-d-[¹⁸F]FPhe exhibited protein incorporation. In benserazide-treated healthy rats, brain uptake after 42–120 min was significantly higher for 3-d-[¹⁸F]FPhe vs. 3-l-[¹⁸F]FPhe. [¹⁸F]FET showed significantly higher uptake into subcutaneous MCF-7 tumors (52–60 min p.i.), while early uptake into orthotopic U87 MG tumors was significantly higher for 3-l-[¹⁸F]FPhe (SUV_max: 3-l-[¹⁸F]FPhe, 107.6 ± 11.3; 3-d-[¹⁸F]FPhe, 86.0 ± 4.3; [¹⁸F]FET, 90.2 ± 7.7). Increased tumoral expression of LAT1 and ASCT2 was confirmed immunohistologically. Conclusion: Both novel tracers enable accurate tumor delineation with an imaging quality comparable to [¹⁸F]FET.

6-l-[¹⁸F]Fluoro-m-tyrosine (6-l-[¹⁸F]FMT) represents a valuable alternative to 6-l-[¹⁸F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson’s disease. However, clinical applications of 6-l-[¹⁸F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[¹⁸F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic Bu₄ONTf using a volatile iPrOH/MeCN mixture as reaction solvent. A simple and fast radiolabeling procedure afforded the tracer in 20.0 ± 3.0% activity yield within 70 min. The developed method was directly implemented onto a modified TracerLab FX C Pro platform originally designed for ¹¹C-labeling. This method enables an uncomplicated switch between ¹¹C- and ¹⁸F-labeling. The simplicity of the developed procedure enables its easy adaptation to other commercially available remote-controlled synthesis units and paves the way for a widespread application of 6-l-[¹⁸F]FMT in the clinic.

Background/Objectives: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly sensitive clinical imaging modalities, frequently employed in conjunction with magnetic resonance imaging (MRI) or computed tomography (CT) for diagnosing a wide range of disorders. Efficient and robust radiolabeling methods are needed to accommodate the increasing demand for PET and SPECT tracer development. Copper-mediated radiohalogenation (CMRH) reactions enable rapid late-stage preparation of radiolabeled arenes, yet synthetic challenges and radiolabeling precursors’ instability can limit the applications of CMRH approaches. Methods: A series of aryl-boronic acids were converted into their corresponding aryl-boronic acid 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] and aryl-boronic acid 1,1,2,2-tetrapropylethylene glycol esters [ArB(Ppin)s] as stable and versatile precursor building blocks for radiolabeling via CMRH. General protocols for the preparation of ¹⁸F-labeled and ¹²³I-labeled arenes utilizing CMRH of these substrates were developed and applied. The radiochemical conversions (RCC) were determined by radio-(U)HPLC. Results: Both ArB(Epin)s and ArB(Ppin)s-based radiolabeling precursors were prepared in a one-step synthesis with chemical yields of 49–99%. Radiolabeling of the aryl-boronic esters with fluorine-18 or iodine-123 via CMRH furnished the corresponding radiolabeled arenes with RCC of 7–99% and 10–99%, respectively. Notably, a radiohalogenated prosthetic group containing a vinyl sulfone motif was obtained with an activity yield (AY) of 18 ± 3%, and applied towards the preparation of two clinically relevant PET tracers. Conclusions: This approach enables the synthesis of stable radiolabeling precursors and thus provides increased versatility in the application of CMRH, thereby supporting the development of novel PET and SPECT radiotracers.

Efficient ¹⁸F-fluorination procedures for the production of radiopharmaceuticals are urgently needed to satisfy the increasing demand for clinical diagnostics using positron emission tomography (PET). However, the development of PET tracers is often a time-consuming and challenging process. This work examines the applicability of the recently described sulfur [¹⁸F]fluoride exchange ([¹⁸F]SuFEx) chemistry as a fast screening approach towards a number of clinically relevant PET tracer preparations. The preparation of a number of ¹⁸F-labeled compounds commenced with [¹⁸F]fluoride loading onto a quarternary methylammonium (QMA) cartridge, which was eluted with a methanolic solution containing a base, followed by solvent removal under reduced pressure. Thereafter, the radiolabeling precursors in MeCN were added to the reaction vessels, and allowed to react via [¹⁸F]SuFEx at room temperature for 5 min. The radiofluorination reactions were quenched by water dilution followed by C18 cartridge purification. The ¹⁸F-labeled products were isolated by elution from the cartridge with EtOH and the identities of the products were confirmed by radio-ultra high performance liquid chromatography (UHPLC). The optimized preparations of ¹⁸F-labeled prostate-specific membrane antigen (PSMA) inhibitor, Programmed death-ligand 1 (PD-L1) ligand, cyclooxygenase-2 inhibitor (COXIB), and Fibroblast activation protein alpha inhibitor (FAPI) were achieved with high non-decay corrected isolated activity yields (AY) of 33–57% (n = 12) and >95% radiochemical purity (RCP) in 25 min. The automated radiosynthesis procedures afforded the radiolabeled products in an unoptimized 8–15% AY (n = 5), with >95% RCP in 40 min. The ultra-fast [¹⁸F]SuFEx reaction permitted several structurally diverse ¹⁸F-labeled compounds for potential imaging to be rapidly achieved in excellent isolated AYs and high RCP. Presently, optimization of the automated radiosynthesis and biological assessment of the ¹⁸F-labeled products is underway.

Clinically used imaging modalities such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) are highly sensitive non-invasive imaging modalities utilized in combination with magnetic resonance imaging (MRI) or computed tomography (CT) for the diagnosis of a multitude of disorders. Efficient and robust radiolabeling methods are needed to accommodate for the increasing demand for PET and SPECT tracer development. Copper-mediated radiohalogenation (CMRH) reactions have been reported for the rapid late-stage preparation of radiolabeled arenes, yet synthetic challenges and instability of corresponding radiolabeling precursors can limit the applications of CMRH radiolabeling approaches. In this work, a general protocol for the preparation of 18F-labeled and 123I-labeled arenes applying CMRH of stable aryl boronate substrates is reported. The method utilizes aryl boronic acid 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] and aryl boronic acid 1,1,2,2-tetrapropylethylene glycol esters [ArB(Ppin)s] as stable and versatile precursor building blocks for radiolabeling via CMRH. Both ArB(Epin)s and ArB(Ppin)s based radiolabeling precursors were prepared in a one-step synthesis from the corresponding aryl boronic acids with chemical yields of 49-99%. Radiolabeling of the aryl boronic esters with fluorine-18 or iodine-123 via CMRH furnished the corresponding radiolabeled arenes with RCC of 7-99% and 10-99%, respectively. Notably, a radiohalogenated prosthetic group containing a vinyl sulfone motif was obtained with an activity yield (AY) of 18 ± 3%, and applied towards the preparation of two clinically-relevant PET tracers.