A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[<sup>18</sup>F]fluoro‐β‐<scp>d</scp>‐arabinofuranosyl)cytosine (<sup>18</sup>F‐FAC)

Meyer, Jan‐Philip; Probst, Katrin C.; Trist, Iuni Margaret Laura; McGuigan, Christopher; Westwell, Andrew D.

doi:10.1002/jlcr.3233

Cited by 6 publications

(5 citation statements)

References 12 publications

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“…The tracer was produced with high chemical and radiochemical purity with late-stage radio-fluorination of the pyrimidine. However, [ 18 F]FAC can be deaminated in vivo by cytidine deaminase [128,129]. The biodistribution data in C57/BL6 mice showed that there is a preferential retention in high dCK-expressing tissue, such as lymphocytes, bonemarrow cells and enterocytes.…”

Section: Dckmentioning

confidence: 99%

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

et al. 2022

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Cancer immunotherapy is an evolving and promising cancer treatment that takes advantage of the body’s immune system to yield effective tumor elimination. Importantly, immunotherapy has changed the treatment landscape for many cancers, resulting in remarkable tumor responses and improvements in patient survival. However, despite impressive tumor effects and extended patient survival, only a small proportion of patients respond, and others can develop immune-related adverse events associated with these therapies, which are associated with considerable costs. Therefore, strategies to increase the proportion of patients gaining a benefit from these treatments and/or increasing the durability of immune-mediated tumor response are still urgently needed. Currently, measurement of blood or tissue biomarkers has demonstrated sampling limitations, due to intrinsic tumor heterogeneity and the latter being invasive. In addition, the unique response patterns of these therapies are not adequately captured by conventional imaging modalities. Consequently, non-invasive, sensitive, and quantitative molecular imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) using specific radiotracers, have been increasingly used for longitudinal whole-body monitoring of immune responses. Immunotherapies rely on the effector function of CD8+ T cells and natural killer cells (NK) at tumor lesions; therefore, the monitoring of these cytotoxic immune cells is of value for therapy response assessment. Different immune cell targets have been investigated as surrogate markers of response to immunotherapy, which motivated the development of multiple imaging agents. In this review, the targets and radiotracers being investigated for monitoring the functional status of immune effector cells are summarized, and their use for imaging of immune-related responses are reviewed along their limitations and pitfalls, of which multiple have already been translated to the clinic. Finally, emerging effector immune cell imaging strategies and future directions are provided.

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Section: Dckmentioning

confidence: 99%

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

et al. 2022

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“…Positron emission tomography [ 17 ] and hyperpolarized metabolic imaging [ 18 ] have already been evaluated in EAE to monitor metabolic changes in the CNS. Still, their widespread use is restricted by the need of specialized equipment to generate the tracers along with their short half-life [ 19 ]. Magnetic resonance spectroscopy (MRS) can detect many of these metabolites without the use of a tracer, but its low sensitivity and low spatial resolution limit its application [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice

Thomas

Yang

Smith

et al. 2022

J Neuroinflammation

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Background Multiple sclerosis (MS) is a neurodegenerative disease, wherein aberrant immune cells target myelin-ensheathed nerves. Conventional magnetic resonance imaging (MRI) can be performed to monitor damage to the central nervous system that results from previous inflammation; however, these imaging biomarkers are not necessarily indicative of active, progressive stages of the disease. The immune cells responsible for MS are first activated and sensitized to myelin in lymph nodes (LNs). Here, we present a new strategy for monitoring active disease activity in MS, chemical exchange saturation transfer (CEST) MRI of LNs. Methods and results We studied the potential utility of conventional (T2-weighted) and CEST MRI to monitor changes in these LNs during disease progression in an experimental autoimmune encephalomyelitis (EAE) model. We found CEST signal changes corresponded temporally with disease activity. CEST signals at the 3.2 ppm frequency during the active stage of EAE correlated significantly with the cellular (flow cytometry) and metabolic (mass spectrometry imaging) composition of the LNs, as well as immune cell infiltration into brain and spinal cord tissue. Correlating primary metabolites as identified by matrix-assisted laser desorption/ionization (MALDI) imaging included alanine, lactate, leucine, malate, and phenylalanine. Conclusions Taken together, we demonstrate the utility of CEST MRI signal changes in superficial cervical LNs as a complementary imaging biomarker for monitoring disease activity in MS. CEST MRI biomarkers corresponded to disease activity, correlated with immune activation (surface markers, antigen-stimulated proliferation), and correlated with LN metabolite levels.

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“…Building on our previous experience of 18 F-radiolabelling of nucleosides for PET imaging [14,15], we set out to apply our technology to the ProTide field. Here we report the first radiosynthetic routes to both 3 -and 2 -fluorinated model ProTides.…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis of [18F]-Labelled Pro-Nucleotides (ProTides)

et al. 2020

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Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min).

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A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[¹⁸F]fluoro‐β‐d‐arabinofuranosyl)cytosine (¹⁸F‐FAC)

Cited by 6 publications

References 12 publications

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice

Radiosynthesis of [18F]-Labelled Pro-Nucleotides (ProTides)

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A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[18F]fluoro‐β‐d‐arabinofuranosyl)cytosine (18F‐FAC)

Cited by 6 publications

References 12 publications

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy

CEST MRI and MALDI imaging reveal metabolic alterations in the cervical lymph nodes of EAE mice

Radiosynthesis of [18F]-Labelled Pro-Nucleotides (ProTides)

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Product

Resources

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A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[¹⁸F]fluoro‐β‐d‐arabinofuranosyl)cytosine (¹⁸F‐FAC)