Positron emission tomography (PET) is an important driver for present day healthcare. Fluorine-18 is the most widely used radioisotope for PET imaging and a thorough overview of the available ...radiochemistry methodology is a prerequisite for selection of a synthetic approach for new fluorine-18 labelled PET tracers. These PET tracers can be synthesised either by late-stage radiofluorination, introducing fluorine-18 in the last step of the synthesis, or by a building block approach (also called modular build-up approach), introducing fluorine-18 in a fast and efficient manner in a building block, which is reacted further in one or multiple reaction steps to form the PET tracer. This review presents a comprehensive overview of the synthesis and application of fluorine-18 labelled building blocks since 2010.
The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of ...2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP 1-13C glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.
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•Glutamine is a primary carbon source for the oncometabolite 2-hydroxyglutarate•2-HG formation from glutamine occurs with fast kinetics in vitro and in vivo•With HP MRI, 2-HG formation from glutamine can be imaged in real time in vivo•Specific inhibition of mIDH in vivo was detected non-invasively using HP 2-HG
Salamanca-Cardona et al. show that glutamine is a primary carbon source for the biosynthesis of the oncometabolite 2-hydroxyglutarate in mutant IDH tumors. They develop a novel hyperpolarized MRI method using glutamine as a probe to detect 2-hydroxyglutarate formation in vivo in real time, non-invasively, and with high specificity.
Purpose
Meta
-
18
Ffluorobenzylguanidine (
18
FmFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine ...transporter. This pilot study investigates the feasibility of
18
FmFBG PET-CT for imaging in neuroblastoma.
Methods
In a prospective, single-centre study, we recruited children with neuroblastoma, referred for
meta
-
123
Iiodobenzylguanidine (
123
ImIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of
123
ImIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of
18
FmFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score.
Results
Twenty paired
123
ImIBG and
18
FmFBG scans were performed in 14 patients (median age 4.9 years,
n
= 13 stage 4 disease and
n
= 1 stage 4S).
18
FmFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for
18
FmFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for
123
ImIBG scanning (84.5 min, SD 10.5),
p
< 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection
18
FmFBG PET-CT. Compared to
123
ImIBG scanning,
18
FmFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on
18
FmFBG PET-CT compared to
123
ImIBG scanning.
Conclusion
Results of this study demonstrate feasibility of
18
FmFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on
18
FmFBG PET-CT compared to
123
ImIBG scanning.
18
FmFBG PET-CT shows promise for future staging and response assessment in neuroblastoma.
Trial registration
Dutch Trial Register NL8152.
Purpose
All clinical
89
Zr-immuno-PET studies are currently performed with the chelator desferrioxamine (DFO). This chelator provides hexadentate coordination to zirconium, leaving two coordination ...sites available for coordination with, e.g., water molecules, which are relatively labile ligands. The unsaturated coordination of DFO to zirconium has been suggested to result in impaired stability of the complex in vivo and consequently in unwanted bone uptake of
89
Zr. Aiming at clinical improvements, we report here on a bifunctional isothiocyanate variant of the octadentate chelator DFO* and the in vitro and in vivo comparison of its
89
Zr-DFO*-mAb complex with
89
Zr-DFO-mAb.
Methods
The bifunctional chelator DFO*-
p
Phe-NCS was prepared from previously reported DFO* and
p
-phenylenediisothiocyanate. Subsequently, trastuzumab was conjugated with either DFO*-
p
Phe-NCS or commercial DFO-
p
Phe-NCS and radiolabeled with Zr-89 according to published procedures. In vitro stability experiments were carried out in saline, a histidine/sucrose buffer, and blood serum. The in vivo performance of the chelators was compared in N87 tumor-bearing mice by biodistribution studies and PET imaging.
Results
In 0.9 % NaCl
89
Zr-DFO*-trastuzumab was more stable than
89
Zr-DFO-trastuzumab; after 72 h incubation at 2-8 °C 95 % and 58 % intact tracer were left, respectively, while in a histidine-sucrose buffer no difference was observed, both products were ≥ 92 % intact. In vivo uptake at 144 h post injection (p.i.) in tumors, blood, and most normal organs was similar for both conjugates, except for skin, liver, spleen, ileum, and bone. Tumor uptake was 32.59 ± 11.95 and 29.06 ± 8.66 % ID/g for
89
Zr-DFO*-trastuzumab and
89
Zr-DFO-trastuzumab, respectively. The bone uptake was significantly lower for
89
Zr-DFO*-trastuzumab compared to
89
Zr-DFO-trastuzumab. At 144 h p.i. for
89
Zr-DFO*-trastuzumab and
89
Zr-DFO-trastuzumab, the uptake in sternum was 0.92 ± 0.16 and 3.33 ± 0.32 % ID/g, in femur 0.78 ± 0.11 and 3.85, ± 0.80 and in knee 1.38 ± 0.23 and 8.20 ± 2.94 % ID/g, respectively. The uptake in bone decreased from 24 h to 144 h p.i. about two fold for the DFO* conjugate, while it increased about two fold for the DFO conjugate.
Conclusions
Zr-DFO*-trastuzumab showed superior in vitro stability and in vivo performance when compared to
89
Zr-DFO-trastuzumab. This makes the new octadentate DFO* chelator a candidate successor of DFO for future clinical
89
Zr-immuno-PET.
Multiple small molecule PET tracers have been developed for the imaging of the epidermal growth factor receptor (EGFR). These tracers target the tyrosine kinase (TK) domain of the receptor and have ...been used for both quantifying EGFR expression and to differentiate between EGFR mutational statuses. However, the approaches for in vivo evaluation of these tracers are diverse and have resulted in data that are hard to compare. In this review, we analyze the historical development of the in vivo evaluation approaches, starting from the first EGFR TK PET tracer
CPD153035 to tracers developed based on TK inhibitors used for the clinical treatment of mutated EGFR expressing non-small cell lung cancer like
Cerlotinib and
Fafatinib. The evaluation of each tracer has been compiled to allow for a comparison between studies and ultimately between tracers. The main challenges for each group of tracers are thereafter discussed. Finally, this review addresses the challenges that need to be overcome to be able to efficiently drive EGFR PET imaging forward.
89Zr-radiolabelled proteins functionalised with desferrioxamine B are a cornerstone of diagnostic positron emission tomography. In the clinical setting, 89Zr-labelled proteins are produced manually. ...Here, we explore the potential of using a microfluidic photochemical flow reactor to prepare 89Zr-radiolabelled proteins. The light-induced functionalisation and 89Zr-radiolabelling of human serum albumin (89ZrZrDFO-PEG3-Et-azepin-HSA) was achieved by flow photochemistry with a decay-corrected radiochemical yield (RCY) of 31.2 ± 1.3% (n = 3) and radiochemical purity >90%. In comparison, a manual batch photoreactor synthesis produced the same radiotracer in a decay-corrected RCY of 59.6 ± 3.6% (n = 3) with an equivalent RCP > 90%. The results indicate that photoradiolabelling in flow is a feasible platform for the automated production of protein-based 89Zr-radiotracers, but further refinement of the apparatus and optimisation of the method are required before the flow process is competitive with manual reactions.
Brigatinib, a tyrosine kinase inhibitor (TKI) with specificity for gene rearranged anaplastic lymphoma kinase (ALK), such as the EML4–ALK, has shown a potential to inhibit mutated epidermal growth ...factor receptor (EGFR). In this study, N-desmethyl brigatinib was successfully synthesized as a precursor in five steps. Radiolabeling with 11Cmethyl iodide produced methylpiperazine-11Cbrigatinib in a 10 ± 2% radiochemical yield, 91 ± 17 GBq/μmol molar activity, and ≥95% radiochemical purity in 49 ± 4 min. Methylpiperazine-11Cbrigatinib was evaluated in non-small cell lung cancer xenografted female nu/nu mice. An hour post-injection (p.i.), 87% of the total radioactivity in plasma originated from intact methylpiperazine-11Cbrigatinib. Significant differences in tumor uptake were observed between the endogenously EML4–ALK mutated H2228 and the control xenograft A549. The tumor-to-blood ratio in H2228 xenografts could be reduced by pretreatment with ALK inhibitor crizotinib. Tracer uptake in EGFR Del19 mutated HCC827 and EML4–ALK fusion A549 was not significantly different from uptake in A549 xenografts.
Radiolabeled amino acids, their derivatives and peptides have a broad scope of application and can be used as receptor ligands, as well as enzyme substrates for many different diseases as ...radiopharmaceutical tracers. Over the past few decades, the application of molecular imaging techniques such as positron emission tomography (PET) has gained considerable importance and significance in diagnosis in today’s advanced health care. Next to that, the availability of cyclotrons and state-of-the-art radiochemistry facilities has progressed the production of imaging agents enabling the preparation of many versatile PET radiotracers. Due to many favorable characteristics of radiolabeled amino acids and peptides, they can be used for tumor staging and monitoring the progress of therapy success, while aromatic amino acids can be employed as PET tracer to study neurological disorders. This review provides a comprehensive overview of radiosynthetic and enzymatic approaches towards carbon-11 amino acids, their analogues and peptides, with focus on stereoselective reactions, and reflects upon their clinical application.
•The transforming growth factor β (TGFβ) pathway is important in disease.•Imaging the TGFβ pathway is vital for understanding its role in disease.•An overview of existing imaging tracers for the TGFβ ...pathway is presented.•The potential for imaging individual components of this pathway is discussed.
The transforming growth factor β (TGFβ) family of cytokines achieves homeostasis through a careful balance and crosstalk with complex signalling pathways. Inappropriate activation or inhibition of this pathway and mutations in its components are related to diseases such as cancer, vascular diseases, and developmental disorders. Quantitative imaging of expression levels of key regulators within this pathway using positron emission tomography (PET) can provide insights into the role of this pathway in vivo, providing information on underlying pathophysiological processes. PET imaging can also be used to study the drug targeting of this pathway and to detect diseases in which this pathway is disturbed. In this review, we provide an overview of PET tracers available to study the TGFβ signalling pathway. In addition, we discuss future imaging targets for this pathway and possible leads for new PET tracers.
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