Search

Novel radiolabelling methods are important for the development of new tracers for positron emission tomography. Direct nucleophilic fluorination of aromatic rings with [18F]fluoride is limited to activated substrates, restricting the application of this approach. Inspired by transition metal-mediated transformations, a fluorine-18 synthon was prepared to supplement the radiolabelling methods available for molecules unsuitable for direct labelling. 2-Bromo-6-[18F]fluoropyridine (denoted [18F]1) was prepared in high yield, and palladium-mediated cross-coupling reactions were exemplified. High incorporation of fluoride and efficient cross-coupling reactions demonstrate that compound [18F]1 holds promise as a new synthon for construction of fluorine-18-labelled molecules via transition metal-mediated reactions. [ABSTRACT FROM AUTHOR]

Several novel phosphoramidites have been prepared by reaction of the primary amines para-vinylaniline, ortho-anisidine, 2-methoxyphenyl(4-vinylbenzyl)amine, 8-aminoquinoline and 3-vinyl-8-aminoquinoline with (S)-1,1′-bi-2-naphthylchlorophosphite, in the presence of base. Rhodium(I) complexes of these phosphoramidites catalyse the asymmetric hydrogenation of dimethylitaconate and dehydroamino acids and esters giving ee values up to 95%. Soluble non-cross linked polymers of the para-vinylaniline and 3-vinyl-8-aminoquinoline-based phosphoramidites have been prepared by free radical co-polymerisation with styrene in the presence of AIBN as initiator. The corresponding [Rh(COD)]+ complexes serve as recyclable catalysts for the asymmetric hydrogenation dimethylitaconate and dehydroamino acids and esters to give ee values up to 80%. [Copyright &y& Elsevier]

Abstract: Two S-[18F]fluoroalkylated diarylguanidines were synthesized and evaluated in vitro as potential tracers for imaging of N-methyl-d-aspartate receptors (NMDARs) with positron emission tomography (PET). [18F]1 and [18F]10 were synthesized by [18F]fluoroethylation and [18F]fluoromethylation of the thiol precursor 6, respectively. [18F]1 is a promising candidate NMDAR PET tracer, with low nanomolar affinity for the NMDA PCP-site, high selectivity and moderate lipophilicity. [Copyright &y& Elsevier]

The classification of prostate cancer (PCa) lesions using Prostate Imaging Reporting and Data System (PI-RADS) suffers from poor inter-reader agreement. This study compared quantitative parameters or radiomic features from multiparametric magnetic resonance imaging (mpMRI) or positron emission tomography (PET), as inputs into machine learning (ML) to predict the Gleason scores (GS) of detected lesions for improved PCa lesion classification. 20 biopsy-confirmed PCa subjects underwent imaging before radical prostatectomy. A pathologist assigned GS from tumour tissue. Two radiologists and one nuclear medicine physician delineated the lesions on the mpMR and PET images, yielding 45 lesion inputs. Seven quantitative parameters were extracted from the lesions, namely T2-weighted (T2w) image intensity, apparent diffusion coefficient (ADC), transfer constant (KTRANS), efflux rate constant (K ep), and extracellular volume ratio (V e) from mpMR images, and SUV mean and SUV max from PET images. Eight radiomic features were selected out of 109 radiomic features from T2w, ADC and PET images. Quantitative parameters or radiomic features, with risk factors of age, prostate-specific antigen (PSA), PSA density and volume, of 45 different lesion inputs were input in different combinations into four ML models - Decision Tree (DT), Support Vector Machine (SVM), k-Nearest-Neighbour (kNN), Ensembles model (EM). SUV max yielded the highest accuracy in discriminating detected lesions. Among the 4 ML models, kNN yielded the highest accuracies of 0.929 using either quantitative parameters or radiomic features with risk factors as input. ML models' performance is dependent on the input combinations and risk factors further improve ML classification accuracy. [Display omitted] • Among 7 quantitative parameters, SUV max correlated best with Gleason score (GS). • Machine learning yielded higher accuracies than using cut-points of parameters. • Quantitative parameters (QP) and radiomic features (RF) as inputs for GS prediction. • K-Nearest Neighbour yielded highest accuracy of 0.929 with QP and RF. • Combinations of parameters, risk factors and models affect classification accuracy. [ABSTRACT FROM AUTHOR]

We report a general method for the labeling of both CF3 and CF2H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective C−F activation to formally substitute fluorine‐19 with fluorine‐18 in a two‐step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2±6.5 % non‐decay corrected isolated activity yields and 12.0±1.7 GBq μmol−1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever‐increasing use of CF3 and CF2H groups in pharmaceuticals makes this method attractive for drug and radiotracer development. [ABSTRACT FROM AUTHOR]

We report a general method for the labeling of both CF3 and CF2H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective C−F activation to formally substitute fluorine‐19 with fluorine‐18 in a two‐step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2±6.5 % non‐decay corrected isolated activity yields and 12.0±1.7 GBq μmol−1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever‐increasing use of CF3 and CF2H groups in pharmaceuticals makes this method attractive for drug and radiotracer development. [ABSTRACT FROM AUTHOR]

The low response rates associated with immune checkpoint inhibitor (ICI) use has led to a surge in research investigating adjuvant combination strategies in an attempt to enhance efficacy. Repurposing existing drugs as adjuvants accelerates the pace of cancer immune therapy research; however, many combinations exacerbate the immunogenic response elicited by ICIs and can lead to adverse immune-related events. Metformin, a widely used type 2 diabetes drug is an ideal candidate to repurpose as it has a good safety profile and studies suggest that metformin can modulate the tumour microenvironment, promoting a favourable environment for T cell activation but has no direct action on T cell activation on its own. In the current study we used PET imaging with [18F]AlF-NOTA-KCNA3P, a radiopharmaceutical specifically targeting KV1.3 the potassium channel over-expressed on active effector memory T-cells, to determine whether combining PD1 with metformin leads to an enhanced immunological memory response in a preclinical colorectal cancer model. Flow cytometry was used to assess which immune cell populations infiltrate the tumours in response to the treatment combination. Imaging with [18F]AlF-NOTA-KCNA3P demonstrated that adjuvant metformin significantly improved anti-PD1 efficacy and led to a robust anti-tumour immunological memory response in a syngeneic colon cancer model through changes in tumour infiltrating effector memory T-cells. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [18F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [18F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [18F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [18F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapeutic adjuvants, such as oxaliplatin (OXA) and 5-fluorouracil (5-FU), that enhance the immune system, are being assessed as strategies to improve durable response rates when used in combination with immune checkpoint inhibitor (ICI) monotherapy in cancer patients. In this study, we explored granzyme B (GZB), released by tumor-associated immune cells, as a PET imaging-based stratification marker for successful combination therapy using a fluorine-18 (18F)-labelled GZB peptide ([18F]AlF-mNOTA-GZP). Methods: Using the immunocompetent CT26 syngeneic mouse model of colon cancer, we assessed the potential for [18F]AlF-mNOTA-GZP to stratify OXA/5-FU and ICI combination therapy response via GZB PET. In vivo tumor uptake of [18F]AlF-mNOTA-GZP in different treatment arms was quantified by PET, and linked to differences in tumor-associated immune cell populations defined by using multicolour flow cytometry. Results: [18F]AlF-mNOTA-GZP tumor uptake was able to clearly differentiate treatment responders from non-responders when stratified based on changes in tumor volume. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumor-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells and GZB+ NK+ cells. Conclusions: [18F]AlF-mNOTA-GZP tumor uptake, driven by changes in immune cell populations expressing GZB, is able to stratify tumor response to chemotherapeutics combined with ICIs. Our results show that, while the immunomodulatory mode of action of the chemotherapies may be different, the ultimate mechanism of tumor lysis through release of Granzyme B is an accurate biomarker for treatment response. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a notoriously difficult cancer to treat. The recent development of immune checkpoint inhibitors has revolutionised HCC therapy; however, successful response is only observed in a small percentage of patients. Biomarkers typically used to predict treatment response in other tumour types are ineffective in HCC, which arises in an immune-suppressive environment. However, imaging markers that measure changes in tumour infiltrating immune cells may supply information that can be used to determine which patients are responding to therapy posttreatment. We have evaluated [18F]AlF-mNOTA-GZP, a radiolabeled peptide targeting granzyme B, to stratify response to ICIs in a HEPA 1-tumours, a syngeneic model of HCC. Posttherapy, in vivo tumour retention of [18F]AlF-mNOTA-GZP was correlated to changes in tumour volume and tumour-infiltrating immune cells. [18F]AlF-mNOTA-GZP successfully stratified response to immune checkpoint inhibition in the syngeneic HEPA 1-6 model. FACS indicated significant changes in the immune environment including a decrease in immune suppressive CD4+ T regulatory cells and increases in tumour-associated GZB+ NK+ cells, which correlated well with tumour radiopharmaceutical uptake. While the immune response to ICI therapies differs in HCC compared to many other cancers, [18F]AlF-mNOTA-GZP retention is able to stratify response to ICI therapy associated with tumour infiltrating GZB+ NK+ cells in this complex tumour microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: Standardized uptake value ratio (SUVr) used to quantify amyloid-β burden from amyloid-PET scans can be biased by variations in the tracer's nonspecific (NS) binding caused by the presence of cerebrovascular disease (CeVD). In this work, we propose a novel amyloid-PET quantification approach that harnesses the intermodal image translation capability of convolutional networks to remove this undesirable source of variability. Methods: Paired MR and PET images exhibiting very low specific uptake were selected from a Singaporean amyloid-PET study involving 172 participants with different severities of CeVD. Two convolutional neural networks (CNN), ScaleNet and HighRes3DNet, and one conditional generative adversarial network (cGAN) were trained to map structural MR to NS PET images. NS estimates generated for all subjects using the most promising network were then subtracted from SUVr images to determine specific amyloid load only (SAβL). Associations of SAβL with various cognitive and functional test scores were then computed and compared to results using conventional SUVr. Results: Multimodal ScaleNet outperformed other networks in predicting the NS content in cortical gray matter with a mean relative error below 2%. Compared to SUVr, SAβL showed increased association with cognitive and functional test scores by up to 67%. Conclusion: Removing the undesirable NS uptake from the amyloid load measurement is possible using deep learning and substantially improves its accuracy. This novel analysis approach opens a new window of opportunity for improved data modeling in Alzheimer's disease and for other neurodegenerative diseases that utilize PET imaging. [ABSTRACT FROM AUTHOR]

Background and purpose: Various blood biomarkers reflecting brain amyloid‐β (Aβ) load have recently been proposed with promising results. However, to date, no comparative study amongst blood biomarkers has been reported. Our objective was to examine the diagnostic performance and cost effectiveness of three blood biomarkers on the same cohort. Methods: Using the same cohort (n = 68), the performances of the single‐molecule array (Simoa) Aβ40, Aβ42, Aβ42/Aβ40 and the amplified plasmonic exosome (APEX) Aβ42 blood biomarkers were compared using amyloid positron emission tomography (PET) as the reference standard. The extent to which these blood tests can reduce the recruitment cost of clinical trials was also determined by identifying amyloid positive (Aβ+) participants. Results: Compared to Simoa biomarkers, APEX‐Aβ42 showed significantly higher correlations with amyloid PET retention values and excellent diagnostic performance (sensitivity 100%, specificity 93.3%, area under the curve 0.995). When utilized for clinical trial recruitment, our simulation showed that pre‐screening with blood biomarkers followed by a confirmatory amyloid PET imaging would roughly half the cost (56.8% reduction for APEX‐Aβ42 and 48.6% for Simoa‐Aβ42/Aβ40) compared to the situation where only PET imaging is used. Moreover, with 100% sensitivity, APEX‐Aβ42 pre‐screening does not increase the required number of initial participants. Conclusions: With its high diagnostic performance, APEX is an ideal candidate for Aβ+ subject identification, monitoring and primary care screening, and could efficiently enrich clinical trials with Aβ+ participants whilst halving recruitment costs. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes. Procedures: We have assessed the ability of a fluorine-labelled peptide, [18F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [18F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations. Results: [18F]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours. Conclusions: [18F]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation. [ABSTRACT FROM AUTHOR]

Purpose: Cancer immunotherapy has shown huge potential in the fight against cancer, but only a small proportion of patients respond successfully to treatment. Non-invasive methods to stratify responders from non-responders are critically important as immune therapies are often associated with immune-related side effects. Currently, conventional clinical imaging modalities do not provide a useful measure of immune therapy efficacy. Sensitive imaging biomarkers that provide information about the tumoural microenvironment may provide useful insights allowing for improved patient management. Procedures: We have assessed the ability of a number of radiopharmaceuticals to non-invasively measure different aspects of the tumour microenvironment and correlated tumour uptake to immune therapy response in a syngeneic model of colon cancer, CT26-WT. Four radiopharmaceuticals, [18F]FDG (a glucose analogue), [18F]FEPPA (a marker for macrophage activation), [18F]FB-IL2 (a marker for CD25+ cells) and [68Ga] Ga-mNOTA-GZP (a marker for granzyme B, the serine protease downstream effector of cytotoxic T cells), were assessed as potential biomarkers to help stratify response to PD-1 monotherapy or combined anti-PD1 and CLTA4 therapy in vivo correlating tumour uptake with changes in tumour-associated immune cell populations. Results: [18F]FDG, [18F]FEPPA and [18F]FB-IL2 (a marker for CD25+ cells) showed limited ability to determine therapy response and showed little correlation to tumour-associated immune cell changes. However, [68Ga] Ga-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells. Conclusions: [68Ga]Ga-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations supporting continued development of granzyme B-based imaging agents for stratification of response to immunotherapy. Early assessment of immunotherapy efficacy with [68Ga]Ga-mNOTA-GZP may allow for the reduction of unnecessary side effects while significantly improving patient management. [ABSTRACT FROM AUTHOR]

Purpose: The analysis of the [11C]PiB-PET amyloid images of a unique Asian cohort of 186 participants featuring overlapping vascular diseases raised the question about the validity of current standards for amyloid quantification under abnormal conditions. In this work, we implemented a novel pipeline for improved amyloid PET quantification of this atypical cohort. Methods: The investigated data correction and amyloid quantification methods included motion correction, standardized uptake value ratio (SUVr) quantification using the parcellated MRI (standard method) and SUVr quantification without MRI. We introduced a novel amyloid analysis method yielding 2 biomarkers: AβL which quantifies the global Aβ burden and ns that characterizes the non-specific uptake. Cut-off points were first determined using visual assessment as ground truth and then using unsupervised classification techniques. Results: Subject's motion impacts the accuracy of the measurement outcome but has however a limited effect on the visual rating and cut-off point determination. SUVr computation can be reliably performed for all the subjects without MRI parcellation while, when required, the parcellation failed or was of mediocre quality in 10% of the cases. The novel biomarker AβL showed an association increase of 29.5% with the cognitive tests and increased effect size between positive and negative scans compared with SUVr. ns was found sensitive to cerebral microbleeds, white matter hyperintensity, volume, and age. The cut-off points for SUVr using parcellated MRI, SUVr without parcellation, and AβL were 1.56, 1.39, and 25.5. Finally, k-means produced valid cut-off points without the requirement of visual assessment. Conclusion: The optimal processing for the amyloid quantification of this atypical cohort allows the quantification of all the subjects, producing SUVr values and two novel biomarkers: AβL, showing important increased in their association with various cognitive tests, and ns, a parameter sensitive to non-specific retention variations caused by age and cerebrovascular diseases. [ABSTRACT FROM AUTHOR]

Specific mutations significantly affect response to epidermal growth factor tyrosine kinase inhibitor (EGFR‐TKI) treatment in lung cancer patients. Identifying patients with these mutations remains a major clinical challenge. EGFR T790M mutation, which conveys resistance to in the present study, [18F]FEWZ was assessed in vitro to determine efficacy relative to the starting compound and in vivo to measure the biodistribution and specificity of binding to EGFR wild‐type, L858R and T790M bearing tumours. [18F]FEWZ is the first evidence of a radiolabeled third generation anilinopyrimidine‐derived tyrosine kinase inhibitor targeting T790M mutation bearing tumours in vivo. [ABSTRACT FROM AUTHOR]

An in situ generated Pd-Cy*Phine catalyst has been successfully applied to the N-arylation of primary and secondary amines, and it exhibited high performance across multiple substrate classes. The performance induced by the meta-terarylphosphine motif of the Cy*Phine ligand for C-N cross-coupling displayed only subtle differences to that of its biarylphosphine congener XPhos. DFT studies demonstrated comparable reaction energetics in the catalytic cycle steps for both Pd-Cy*-Phine and Pd-XPhos, which was consistent with previous findings. The computational investigation also indicated that a putative rate-determining step occurred after amine binding, which was likely to have annulled the expected benefits of having a meta-terarylphosphine ligand architecture. [ABSTRACT FROM AUTHOR]

A methodology for a sequential palladium-catalyzed cross-coupling procedure consisting of borylation, the Suzuki reaction and amination has been developed for the assembly of molecules with multi-aryl backbones. The linchpin of this development is the meta-terarylphosphine ligand, Cy*Phine, which has been employed as an air- and moisture-stable precatalyst, Pd(Cy*Phine)2Cl2, to improve the efficiency of one-pot borylation-Suzuki reactions. Additionally, the reactivity of the Pd-Cy*Phine system could be tuned to furnish a one-pot, borylation-Suzuki reaction-amination (BSA) cross-coupling treble. The methodology successfully integrated complementary conditions for three distinctly different and modular reactions. Average yields of 74-94% could be achieved for each segment that cumulatively afforded 50-84% yield over the entire three-step sequence in a single pot. [ABSTRACT FROM AUTHOR]

The PCYP-catalyzed decarboxylative cross-coupling of chlorides (I), (IV), and (VIII) with 3-substituted propiolic acids (II) gives rise to unsymmetrically disubstituted alkynes (III), (V), and (IX) in high yields. [ABSTRACT FROM AUTHOR]

Fluorinases offer an environmentally friendly alternative for selective fluorination under mild conditions. However, their diversity is limited in nature and they have yet to be engineered through directed evolution. Herein, we report the directed evolution of the fluorinase FlA1 for improved conversion of the non-native substrate 5′-chloro-5′-deoxyadenosine (5′-ClDA) into 5′-fluoro-5′-deoxyadenosine (5′-FDA). The evolved variants, fah2081 (A279Y) and fah2114 (F213Y, A279L), were successfully applied in the radiosynthesis of 5′-[18F]FDA, with overall radiochemical conversion (RCC) more than 3-fold higher than wild-type FlA1. Kinetic studies of the two-step reaction revealed that the variants show a significantly improved kcat value in the conversion of 5′-ClDA into S-adenosyl- l-methionine (SAM) but a reduced kcat value in the conversion of SAM into 5′-FDA. [ABSTRACT FROM AUTHOR]

Fluorinases offer an environmentally friendly alternative for selective fluorination under mild conditions. However, their diversity is limited in nature and they have yet to be engineered through directed evolution. Herein, we report the directed evolution of the fluorinase FlA1 for improved conversion of the non-native substrate 5′-chloro-5′-deoxyadenosine (5′-ClDA) into 5′-fluoro-5′-deoxyadenosine (5′-FDA). The evolved variants, fah2081 (A279Y) and fah2114 (F213Y, A279L), were successfully applied in the radiosynthesis of 5′-[18F]FDA, with overall radiochemical conversion (RCC) more than 3-fold higher than wild-type FlA1. Kinetic studies of the two-step reaction revealed that the variants show a significantly improved kcat value in the conversion of 5′-ClDA into S-adenosyl- l-methionine (SAM) but a reduced kcat value in the conversion of SAM into 5′-FDA. [ABSTRACT FROM AUTHOR]

The reaction mechanism for the in situ prepared Pd-Cy*Phine catalyst used in copper-free Sonogashira coupling was investigated using density functional theory. In addition, the significance of the meta-terarylphosphine ligand architecture of Cy*Phine was probed, as it had been previously shown experimentally to augment catalytic activity relative to its biarylphosphine analogue, XPhos. The calculated reaction barriers and free energies for the steps in the catalytic cycle suggest that the suppression of a dearomative rearrangement pathway is likely to be an important feature for the improved catalytic performance observed for the Pd-Cy*Phine system. [ABSTRACT FROM AUTHOR]

The evolutionary mffa-terarylphosphine ligand architecture of Cy*Phine was recently shown to be a key feature that imposed outstanding performance in palladium-catalyzed copper-free Sonogashira applications. Herein, the Pd-Cy*Phine combination has similarly proven to be a powerful catalyst system for the Mizoroki-Heck reaction. Using high-throughput screening (HTS) methodology, DMF and NaHCO3 were rapidly identified as the most effective solvent and base pair for the cross-coupling catalysis of challenging and industrially valuable substrates including highly electron-rich heteroaryl bromides and unactivated olefins. Unprotected functional groups were well tolerated using low catalyst loadings, and the simple protocol produced excellent yields (up to 99%) with unprecedented substrate diversity. The Pd- Cy*Phine system broadly outperformed many state-of-the-art commercial alternatives, which demonstrated its potential as a next-generation cross-coupling catalyst. [ABSTRACT FROM AUTHOR]

A novel meta-terarylphosphine ligand, Cy*Phine, was developed and found to be a highly active promoter of copper-free Sonogashira cross-coupling reactions when combined in situ with a palladium source. The evolutionary m-terarylphosphine ligand architecture was able to impose significant performance advantages over its biarylphosphine congeners. An expedient and versatile protocol was also devised with an emphasis on substrates applicable to the fine-chemicals industry by featuring a diverse range of challenging, electron-rich aryl chlorides and terminal alkynes. The Pd-Cy*Phine catalyst was able to deliver products in excellent yields with efficient substrate utilization, which minimizes the generation of commonly formed byproducts, and the reaction is tolerant of a variety of substrates with unprotected functional groups. [ABSTRACT FROM AUTHOR]

Abstract: An intravascular MRI contrast agent Gd(DO3A-Lys), Gadolinium(III) (2,2′,2″-(10-(3-(5-benzamido-6-methoxy-6-oxohexylamino)-3-oxopropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate), has been studied for tumor angiography based on its high relaxivity and long blood half-life. The preparation procedures of the contrast agent have been modified in order to achieve higher yield and improve the synthetic reproducibility. High relaxivity of Gd(DO3A-Lys) has been confirmed by measurements at 3 T, 7 T and 9.4 T magnetic fields. The relaxivity-dependent albumin binding study indicated that Gd(DO3A-Lys) partially bound to albumin protein. In vitro cell viability in HK2 cell indicated low cytotoxicity of Gd(DO3A-Lys) up to 1.2 mm [Gd] concentration. In vivo toxicity studies demonstrated no toxicity of Gd(DO3A-Lys) on kidney tissues up to 0.2 mm [Gd]. While the toxicity on liver tissue was not observed at low dosage (1.0 mm [Gd]), Gd(DO3A-Lys) cause certain damage on hepatic tissue at high dosage (2.0 mm [Gd]). The DO3A-Lys has been labeled with 68Ga radioisotope for biodistribution studies. 68Ga(DO3A-Lys) has high uptake in both HT1080 and U87MG xenograft tumors, and has high accumulation in blood. Contrast-enhanced MR angiography (CE-MRA) in mice bearing U87MG xenograft tumor demonstrated that Gd(DO3A-Lys) could enhance vascular microenvironment around the tumor, and displays promising characteristics of an MRI contrast agent for tumor angiography. [Copyright &y& Elsevier]

Simple Summary: Cancer immunotherapy has shown huge potential in the fight against cancer but few patients respond durably to treatment. Durable immunological responses are associated with the generation of memory T cells. A subset of memory T cells, effector memory T cells, have been shown to be associated with tumours responding to immune checkpoint inhibitor therapy in a range of cancer types. These effector memory T cells overexpress the potassium channel, Kv1.3, on the cell surface. In the current manuscript, we have developed a new Kv1.3 targeting peptide radiopharmaceutical, [18F]AlF-NOTA-KCNA3P, and characterised its in vivo biodistribution and ability to stratify response to immune checkpoint inhibitor therapy, correlating tumour uptake to changes in tumour associated immune cell populations. Overall, [18F]AlF-NOTA-KCNA3P successfully predicted response to immune checkpoint inhibitors in a murine model of colon cancer where tracer uptake in the tumour correlated well with changes in tumour associated memory T cell populations. Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer; however, only a relatively small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated with the generation of memory T cells. Effector memory T cells associated with tumour response to immune therapies are characterized by substantial upregulation of the potassium channel Kv1.3 after repeated antigen stimulation. We have developed a new Kv1.3 targeting radiopharmaceutical, [18F]AlF-NOTA-KCNA3P, and evaluated whether it can reliably differentiate tumours successfully responding to immune checkpoint inhibitor (ICI) therapy targeting PD-1 alone or combined with CLTA4. In a syngeneic colon cancer model, we compared tumour retention of [18F]AlF-NOTA-KCNA3P with changes in the tumour immune microenvironment determined by flow cytometry. Imaging with [18F]AlF-NOTA-KCNA3P reliably differentiated tumours responding to ICI therapy from non-responding tumours and was associated with substantial tumour infiltration of T cells, especially Kv1.3-expressing CD8+ effector memory T cells. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel TSPO ligands based on the tetracyclic class of translocator protein (TSPO) ligands first described by Okubo et al. was synthesised and evaluated as potential positron emitting tomography (PET) ligands for imaging TPSO in vivo. Fluorine-18 labelling of the molecules was achieved using direct radiolabelling or synthon based labelling approaches. Several of the ligands prepared have promising profiles as potential TSPO PET imaging ligands. [Copyright &y& Elsevier]

Abstract: We report here a radiosynthesis for the D2/3 agonist (+)-4-([3-11C]propyl)-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (3-[11C]-(+)-PHNO) labelled at the terminal carbon of the N-propyl chain. The protocol is based on 11C-methylation of an N-acetyl precursor. This initial step is followed by a reduction with LiAlH4 to give ([3-11C]-(+)-PHNO). We first applied the method for the synthesis of a model compound, N-3-([11C]propyl)-1,2,3,4-tetrahydroisoquinoline, which we obtained in 77–97% analytical radiochemical yield (n=6) in 20min. Similarly, we prepared ([3-11C]-(+)-PHNO) in 55–60% analytical radiochemical yield (n=5) using a one-pot procedure. We have also been able to implement the complete process on a semi-automated module. This platform delivered purified and formulated [3-11C]PHNO with an average radiochemical yield of 9% (n=13, range 2–30%, non-decay corrected), a radiochemical purity >95%, and a specific radioactivity of 26.8–81.1GBq/μmol in a total time of 63–65min. [Copyright &y& Elsevier]

Integrins have become increasingly attractive targets for molecular imaging of angiogenesis with positron emission tomography or single-photon emission computed tomography, but the reliable production of radiopharmaceuticals remains challenging. A strategy for chemoselective labeling of the integrin ligand-c(RGDyK) peptide-has been developed on the basis of the Cu(I)-catalyzed conjugation reaction. Recently, we reported a nucleophilic detagging and fluorous solid-phase extraction method providing an easy way to implement an approach for obtaining 2-[18F]fluoroethyl azide. In this work, we report the practical use of this method for the preparation of the 2-[18F]fluoroethyl-triazolyl conjugated c(RGDyK) peptide: [18F]FtRGD. The two-step, two-pot synthesis, HPLC purification, and reformulation could be readily performed with a standard nucleophilic radiofluorination synthesizer (GE TRACERlab FXFN), with minimal modifications. [18F]FtRGD was obtained in a solution for injection (>500 MBq/mL) in 10-30% nondecay-corrected radiochemical yield, excellent radiochemical purity (>98%), and 28 ± 13 GBq/µmol specific activity. [18F]FtRGD ( Ki = 54 ± 14 nM for αVβ3 and 1.7 ± 0.2 nM for αV β5) was evaluated in mice and showed good stability in vivo, good tumor-to-background ratio (1.6 ± 0.3 %ID/g at 1.5 h post-injection in U87-MG tumors), and rapid urinary excretion. Therefore, [18F]FtRGD proved valuable for preclinical positron emission tomography imaging of integrin expression. [ABSTRACT FROM AUTHOR]

Abstract: A series of organic cations, such as triphenylphosphonium (TPP), 2-(diphenylphosphoryl)-ethyldiphenylphosphonium (TPEP), represent molecular probes for imaging tumors. These organic cations have been labeled with 64Cu radioisotope for imaging tumors by positron emission tomograghy (PET). Among these organic cation ligands, TPEP was selected for extensive evaluation using magnetic resonance imaging (MRI) based on its higher tumor uptake and better Tumor/Background (T/B) ratios. This report presents the development of a new Gd(III) chelate [Gd(DO3A-xy-TPEP)]+ as a cationic MRI contrast agent. The contrast agent was synthesized and characterized in vitro and in vivo. In vitro cell viability showed low cytotoxicity at low [Gd] concentrations. Cell uptake experiment shows that the [Gd(DO3A-xy-TPEP)]+ has high affinity for tumor cells. The in vitro T 1 relaxivity measured at 9.4 T is about 50% higher than those of contrast agents in clinical use: Gd-DTPA (Magnevist) and Gd-DOTA (Dotarem). In vivo imaging studies in tumor-bearing mice at 7.0 T demonstrated significant signal enhancement at the site of the tumors. [Gd(DO3A-xy-TPEP)]+ is a promising tumor-targeting MRI contrast agent for diagnostic imaging. [Copyright &y& Elsevier]

18F-labelled fluoroalkylamines are attractive reagents for the preparation of positron emission tomography tracers containing amine, amide, and N-heterocyclic moieties. Herein, we report that 2-[18F]fluoroethylamine can be obtained from 2-[18F]fluoroethyl azide by reduction with elemental copper under acidic conditions. Azide to amine reduction was achieved in near quantitative analytical yields within 30 min by heating a solution of 2-[18F]fluoroethyl azide in the presence of copper wire and aqueous trifluoroacetic acid. Subsequent reaction of 2-[18F]fluoroethylamine with benzoyl chloride in the presence of triethylamine provided N-[18F]fluoroethyl benzamide in 63% decay-corrected radiochemical yield from 2-[18F]fluoroethyl azide. The utility of the Cu(0)/H+ azide reduction method was further exemplified by preparation of the potential GABAA tracer 9 H-β-carboline N-2-[18F]fluoroethylamide, which was obtained in 46% decay-corrected radiochemical yield by reaction of 2-[18F]fluoroethylamine with the corresponding 9 H-β-carboline pentafluorophenyl ester. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: A novel class of alkyne linked [Tyr3]octreotate analogues have been labelled by a copper catalysed azide-alkyne cycloaddition reaction (CuAAC) to form a 1,4-substituted triazole using the reagent [18F]2-fluoroethyl azide. An unexpected variability in reactivity during the CuAAC reaction was observed for each alkyne analogue which has been investigated. Two lead alkyne linked [Tyr3]octreotate analogues, G-TOCA (3a) and βAG-TOCA (5a) have been identified to be highly reactive in the click reaction showing complete conversion to the [18F]2-fluoroethyl triazole linked [Tyr3]octreotate analogues FET-G-TOCA (3b) and FET-βAG-TOCA (5b) under mild conditions and with short synthesis times (5min at 20°C). As well as ease of synthesis, in vitro binding to the pancreatic tumour AR42J cells showed that both FET-G-TOCA and FET-βAG-TOCA have high affinity for the somatostatin receptor with IC50 of 4.0±1.4, and 1.6±0.2nM, respectively. [Copyright &y& Elsevier]

Abstract: Introduction: Choline radiotracers are widely used for clinical PET diagnosis in oncology. [11C]Choline finds particular utility in the imaging of brain and prostate tumor metabolic status, where 2-[18F]fluoro-2-deoxy-d-glucose (‘FDG’) shows high background uptake. More recently we have extended the clinical utility of [11C]choline to breast cancer where radiotracer uptake correlates with tumor aggressiveness (grade). In the present study, a new choline analog, [18F]fluoro-[1,2-2H4]choline, was synthesized and evaluated as a potential PET imaging probe. Methods: [18F]Fluorocholine, [18F]fluoro-[1-2H2]choline and [18F]fluoro-[1,2-2H4]choline were synthesized by alkylation of the relevant precursor with [18F]fluorobromomethane or [18F]fluoromethyl tosylate. Radiosynthesis of [18F]fluoromethyl tosylate required extensive modification of the existing method. [18F]Fluorocholine and [18F]fluoro-[1,2-2H4]choline were then subjected to in vitro oxidative stability analysis in a chemical oxidation model using potassium permanganate and an enzymatic model using choline oxidase. The two radiotracers, together with the corresponding di-deuterated compound, [18F]fluoro-[1-2H2]choline, were then evaluated in vivo in a time-course biodistribution study in HCT-116 tumor-bearing mice. Results: Alkylation with [18F]fluoromethyl tosylate proved to be the most reliable radiosynthetic route. Stability models indicate that [18F]fluoro-[1,2-2H4]choline possesses increased chemical and enzymatic (choline oxidase) oxidative stability relative to [18F]fluorocholine. The distribution of the three radiotracers, [18F]fluorocholine, [18F]fluoro-[1-2H2]choline and [18F]fluoro-[1,2-2H4]choline, showed a similar uptake profile in most organs. Crucially, tumor uptake of [18F]fluoro-[1,2-2H4]choline was significantly increased at late time points compared to [18F]fluorocholine and [18F]fluoro-[1-2H2]choline. Conclusions: Stability analysis and biodistribution suggest that [18F]fluoro-[1,2-2H4]choline warrants further in vivo investigation as a PET probe of choline metabolism. [Copyright &y& Elsevier]

Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting. [ABSTRACT FROM AUTHOR]

The compound [Rh(COE)2(acac)] (1) is a catalyst precursor in its own right, and a starting material for the preparation of other catalyst precursors for use in a variety of reactions such as hydroboration, diboration and the addition of arylboronic acids to aldehydes. Although a preparation using Tl(acac) and [Rh(COE)2(μ-Cl)]2 is in the literature, it would appear that it is not widely known and we have received several requests for our synthetic protocol for 1, which does not use any thallium salts. We present herein a synthesis of 1 from [Rh(COE)2(μ-Cl)]2 and Na(acac), along with its full spectroscopic and structural characterisation. The single crystal X-ray structure of 1 indicates approximate square-planar geometry at Rh, with the two olefinic C&z.dbnd6;C bonds lying perpendicular to the square plane. [Copyright &y& Elsevier]

The Ag-mediated electrophilic [18F]fluorination of an arylboronic ester is reported. This new radiochemical transformation uses [18F]selectfluor bis(triflate) in acetone. The process gave 6-[18F]fluoro-l-DOPA with a RCY of 19 ± 12% and a specific activity of 2.6 ± 0.3 GBq μmol−1. [ABSTRACT FROM AUTHOR]

The reaction has been successfully applied in the synthesis of pharmaceutical drug eletriptan (XVI), which is used in treatment of migraine headaches. [ABSTRACT FROM AUTHOR]

The novel title ligand TAP, when combined in situ with a Pd-source [cf. [ABSTRACT FROM AUTHOR]