Browsing by Author "Roberts, MP"

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    Ascertaining the suitability of aryl sulfonyl fluorides for [18F]radiochemistry applications: a systematic investigation using microfluidics
    (American Chemical Society, 2013-10-18) Matesic, L; Wyatt, NA; Fraser, BH; Roberts, MP; Pham, TQ; Greguric, I
    Optimization of [18F]radiolabeling conditions and subsequent stability analysis in mobile phase, PBS buffer, and rat serum of 12 aryl sulfonyl chloride precursors with various substituents (electron-withdrawing groups, electron-donating groups, increased steric bulk, heterocyclic) were performed using an Advion NanoTek Microfluidic Synthesis System. A comparison of radiochemical yields and reaction times for a microfluidics device versus a conventional reaction vessel is reported. [18F]Radiolabeling of sulfonyl chlorides in the presence of competing nucleophiles, H-bond donors, and water was also assessed and demonstrated the versatility and potential utility of [18F]sulfonyl fluorides as synthons for indirect radiolabeling. © 2013 American Chemical Society
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    Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter
    (Elsevier B. V., 2019-01) Fraser-Spears, R; Krause-Heuer, AM; Basiouny, M; Mayer, FP; Manishimwe, M; Wyatt, NA; Dobrowolski, JC; Roberts, MP; Greguric, I; Kumar, N; Koek, W; Sitte, HH; Callaghan, PD; Fraser, BH; Daws, LC
    Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for α1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [3H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [3H]citalopram, [3H]nisoxetine and [3H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high-capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders. © 2021 Elsevier B.V.
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    Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22
    (Elsevier B. V., 2017-09-08) Krause-Heuer, AM; Fraser-Spears, R; Dobrowolski, JC; Ashford, ME; Wyatt, NA; Roberts, MP; Gould, GG; Cheah, WC; Ng, CKL; Bhadbhade, MM; Zhang, B; Greguric, I; Wheate, NJ; Kumar, N; Koek, W; Callaghan, PD; Daws, LC; Fraser, BH
    Antidepressant-like activity Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1–7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1–7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined. © 2017 Elsevier B.V.
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    Radiosynthesis and ‘click’ conjugation of ethynyl‐4‐[18F]fluorobenzene — an improved [18F]synthon for indirect radiolabeling
    (John Wiley and Sons, 2015-11-03) Roberts, MP; Pham, TQ; Doan, J; Jiang, CD; Hambley, TW; Greguric, I; Fraser, BH
    Reproducible methods for [18F]radiolabeling of biological vectors are essential for the development of new [18F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi-step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [18F]radiolabeling of such molecules, our group has synthesized ethynyl-4-[18F]fluorobenzene ([18F]2, [18F]EYFB) in a single step (14 ± 2% non-decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne-functionalized synthon [18F]2 was then conjugated to two azido-functionalized vector molecules via CuAAC reactions. The first ‘proof of principle’ conjugation of [18F]2 to 1-azido-1-deoxy-β-d-glucopyranoside (3) gave the desired radiolabeled product [18F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [18F]2 to matrix-metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [18F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [18F]4 and [18F]6 including [18F]F− drying, two-step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [18F]2 and the conjugated products, [18F]4 and [18F]6, were all greater than 98%. The specific activities of [18F]2 and [18F]6 were low, 5.97 and 0.17 MBq nmol−1, respectively. © 2015 John Wiley & Sons, Ltd.
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    Radiosynthesis of [18F]-ethynyl-4-fluorobenzene for click conjugation
    (John Wiley & Sons, Inc, 2013-05-09) Roberts, MP; Pham, TQ; Doan, J; Fraser, BH; Hambley, TW; Greguric, I
    Objectives: Fluorine-18 is the most commonly utilised PET nuclide due to its favourable characteristics including 110 min half-life, low positron energy and ease of availability. Unfavourable harsh reaction conditions required for direct labelling have led to the development of indirect labelling methods; including the use of the alkyne-azide copper(I) catalysed cycloaddition (CuAAC) ‘click’ reaction. We have investigated the one-step radiolabelling of a suitable precursor, 4-ethynyl-N,N,N-trimethylbenzenaminium triflate (1), particularly to probe the usefulness of the trimethylammonium leaving group, and developed a novel [18F]-alkynyl synthon (2) that has successfully been conjugated to an azido-sugar (3, R1) and azido-peptide mimetic (3, R2). Methods: Radiosynthesis (Figure 1) was achieved by reacting 4-ethynyl-N,N,N-trimethylbenzenaminium triflate (1) with activated K18F.K222 complex, in DMF at 150 °C for 5 minutes, via standard nucleophilic substitution, following HPLC purification to afford [18F]-ethynyl-4-fluorobenzene (2). The collected [18F]-synthon (2) was concentrated by passing through a reverse phase C18 Sep-Pak® Plus cartridge and then standard click reaction conditions were utilised by first eluting the [18F]-synthon with acetonitrile into a reaction vial containing copper(I) iodide, sodium ascorbate, lutidine and the azido derivative of choice in a water/acetonitrile mixture. The reaction was heated at 85 °C for 10 minutes and purified by HPLC to obtain the clicked derivative (3). FNNNNOTfF18H18FK222, K2CO3DMF, 150 °C,5 minazido-RCuINa-ascorbatelutidineACN/H2O 50%80 °C, 10 min18ROHNHOOHOHNONHR2=R1=OHOOHHOOH(1)(2)(3) Results: 4-Ethynyl-N,N,N-trimethylbenzenaminium triflate (1) was successfully labelled in 15-20% yield (non-decay corrected) after HPLC purification. In attempt to by-pass purification by HPLC a C18 Sep-Pak® was also attempted, however the decreased purity obtained resulted in decreased conjugation yields. The reasonably low yield of [18F]-ethynyl-4-fluorobenzene (2) is attributed to the competing [18]F-substitution on the trimethyl ammonium group forming [18F]-methylfluoride rather than the desired aromatic labelling. The alkynyl synthon (2) was successfully conjugated to 2 small molecules (a sugar and a peptide mimetic) using traditional CuAAC conditions. Conclusions: We have synthesised a new [18F]-labelled alkynyl synthon that was successfully clicked to two azido derivatives in adequate yield. Future work involves modification of the synthon with more activating substituents to decrease the competing [18F]-methylfluoride production and consequently increase the desired click conjugation yield. In addition we intend to further investigate other forms of cartridge purification. © 2013 John Wiley & Sons, Ltd.
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    SP-103 - Scandium-47 and lutetium-177 radiolabelling and stability studies of 1st and 2nd generation DOTA-triphenylphosphonium ligands – potential radionuclide theranostics for treatment of glioblastoma multi-forme
    (Elsevier, 2021-05-17) Wyatt, NA; Hogan, L; Pellegrini, PA; Roberts, MP; Hall, A; Smith, N; Hemzal, E; Hill, L; Howell, NR; Middleton, RJ; Safavi-Naeini, M; Rendina, LM; Fraser, BH
    Scandium-47 has emerged as a promising radioisotope for targeted radionuclide tumor therapy. This is due, to a significant extent, from the combination of low energy / short range β- emission, the availability of a “perfect theranostic pair” with Sc-44 for companion PET imaging, the potential to form highly stable radiometal complexes, and the availability of suitable γ emissions for companion SPECT imaging. Sc-47 also has a shorter half-life (3.35 d) than the chemically similar Lu-177 (6.7 d) which is significant given recent in vitro research that suggests longer lived isotopes require more initial radioactivity to have the same effect upon cell viability [3]. The shorter half-life of Sc-47 also suggests it may be more suitable for smaller biological vectors (with shorter biological half-lives) such as small molecules and low MW peptides. One area of clinical treatment where Sc-47 can have impact and where improvements in patient outcomes and survival rates remain stubbornly low is glioblastoma multiforme (GBM). GBM is the most common and aggressive form of malignant brain tumor and represents around 60% of all adult brain tumors with a global incidence of <10 per 100,000 persons. The prognosis for GBM patients is poor with a -ear survival rate of 37%, 5 year rate of 5% and a median survival time of 10 months. The current standard of treatment is resection of the tumor followed by radiation therapy and chemotherapy. Given this poor prognosis there is a clear and unmet need for improved classes of treatment. Although significant progress has been made towards bringing GBM targeted radionuclide therapies to the clinic, the efforts to date have not included utilizing Sc-44/ Sc-47. Given this we are developing and evaluating Sc-44/Sc-47 and Lu-177/Ga-68 radiolabelled triphenylphosphonium (TPP) functionalised DOTA ligands (1st and 2nd generation) as potential theranostics for GBM. Described herein is our work on comparing the radiolabelling efficiency (Sc-47 vs. Lu-177) and stability studies (PBS pH 7.4, rat plasma) for our 1st and 2nd generation DOTA-TPP ligands. The presence of an additional carbonyl group in the 2nd generation DOTATPP ligand was anticipated to increase the number of donor atoms around the radiometal and affect radiolabelling reaction conditions and, more importantly, increase radiometal complex stability. Copyright © 2021 Elsevier Inc.
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    Synthesis and in vivo evaluation of [123I]melanin-targeted agents
    (American Chemical Society, 2015-08-15) Roberts, MP; Nguyen, VH; Ashford, ME; Berghofer, PJ; Wyatt, NA; Krause-Heuer, AM; Pham, TQ; Taylor, SR; Hogan, L; Jiang, CD; Fraser, BH; Lengkeek, NA; Matesic, L; Grégoire, MC; Denoyer, D; Hicks, RJ; Katsifis, A; Greguric, I
    This study reports the synthesis, [123I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [131I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60–90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [123I]4 (ICF01012). The most favorable compounds ([123I]20, [123I]23, [123I]41, and [123I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [123I]20 and [123I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [123I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [123I]41 and [123I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [123I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [131I] therapeutic evaluation. ©2015, American Chemical Society