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Dearling J.L.J.,Boston Childrens Hospital | Dearling J.L.J.,Harvard University | Barnes J.W.,Harvard University | Barnes J.W.,Dana-Farber Cancer Institute | And 16 more authors.
Nuclear Medicine and Biology | Year: 2013

Introduction: The αvβ3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of αvβ3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with αvβ3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with 99mTc. In an effort to begin to address this limitation, we evaluated the tumor uptake of 99mTc-NC100692, a cyclic RGD peptide that binds to αvβ3 with ~1-nM affinity, in an αvβ3-positive tumor model as well as its in vivo specificity. Methods: MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for αvβ3, to block and displace 99mTc-NC100692 in an orthotopic U87 glioma tumor. The specificity of 99mTc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of 99mTc-NC100692 with that of the non-specific structural analogue 99mTc-AH-111744 and by blocking uptake of 99mTc-NC100692 with excess unlabeled NC100692. Results: MicroSPECT imaging studies demonstrated that uptake of 99mTc-NC100692 in the intracranial tumor model was both blocked and displaced by the αvβ3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of 99mTc-NC100692 at 1h post-injection was 2.8±0.7% ID/g compared to 0.38±0.1% ID/g for 99mTc-AH-111744 (p<0.001). Blocking 99mTc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68±0.3% ID/g (p=0.01). Conclusion: These results confirm that 99mTc-NC100692 does, in fact, target the αvβ3 integrin and may, therefore, be useful in identifying patients prior to anti-αvβ3 therapy as well as monitoring the response of these patients to therapy. © 2013 Elsevier Inc.

Fortt R.,Imanet | Smith G.,Imperial College London | Smith G.,University of Hull | Awais R.O.,Imanet | And 2 more authors.
Nuclear Medicine and Biology | Year: 2012

Introduction: Isatin-5-sulfonamide ([18F]ICMT-11) is a sub-nanomolar inhibitor of caspase-3 previously evaluated as an apoptosis imaging agent. Herein, an alternative radiosynthesis of [18F]ICMT-11 with increased purity and specific activity is presented. Finally, a GMP-applicable automated radiosynthesis of [18F]ICMT-11 is described. Methods: The preparation of [18F]ICMT-11 was evaluated under a variety of reaction conditions, including reaction solvent, by employing alternative phase transfer catalysts and under different deprotection conditions. Following initial investigations, the process was transferred onto a fully automated GE FASTlab synthesis platform for further development and optimisation. Results: The synthesis of [18F]ICMT-11 was successfully validated under GMP conditions, resulting in a yield of 4.6±0.4GBq with a radiochemical purity of >98% at EOS and a specific activity of 685±237GBq/μmol within 90 min. Quality control was carried out in accordance with the European Pharmacopoeia and demonstrated that [18F]ICMT-11 can be consistently manufactured on the FASTlab to meet specifications. Conclusions: A simplified methodology for the synthesis of the apoptosis imaging agent, [18F]ICMT-11, has been achieved by the SN2 displacement of a tosylate leaving group with [18F]fluoride ion. This results in an increased purity and specific activity over the original copper catalysed "Click" synthetic stratagem reaction involving 2-[18F]fluoroethylazide with an alkyne precursor and is now suitable for routine clinical application. © 2012 Elsevier Inc.

Morris O.,University of Manchester | McMahon A.,University of Manchester | Boutin H.,University of Manchester | Grigg J.,The Grove Center | Prenant C.,University of Manchester
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2016

[18F]Fluoroacetaldehyde is a biocompatible prosthetic group that has been implemented pre-clinically using a semi-automated remotely controlled system. Automation of radiosyntheses permits use of higher levels of [18F]fluoride whilst minimising radiochemist exposure and enhancing reproducibility. In order to achieve full-automation of [18F]fluoroacetaldehyde peptide radiolabelling, a customised GE Tracerlab FX-FN with fully programmed automated synthesis was developed. The automated synthesis of [18F]fluoroacetaldehyde is carried out using a commercially available precursor, with reproducible yields of 26% ± 3 (decay-corrected, n = 10) within 45 min. Fully automated radiolabelling of a protein, recombinant human interleukin-1 receptor antagonist (rhIL-1RA), with [18F]fluoroacetaldehyde was achieved within 2 h. Radiolabelling efficiency of rhIL-1RA with [18F]fluoroacetaldehyde was confirmed using HPLC and reached 20% ± 10 (n = 5). Overall RCY of [18F]rhIL-1RA was 5% ± 2 (decay-corrected, n = 5) within 2 h starting from 35 to 40 GBq of [18F]fluoride. Specific activity measurements of 8.11–13.5 GBq/µmol were attained (n = 5), a near three-fold improvement of those achieved using the semi-automated approach. The strategy can be applied to radiolabelling a range of peptides and proteins with [18F]fluoroacetaldehyde analogous to other aldehyde-bearing prosthetic groups, yet automation of the method provides reproducibility thereby aiding translation to Good Manufacturing Practice manufacture and the transformation from pre-clinical to clinical production. Copyright © 2016 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons, Ltd.

Virgincar R.S.,Duke University | Cleveland Z.I.,Duke University | Sivaram Kaushik S.,Duke University | Freeman M.S.,Duke University | And 9 more authors.
NMR in Biomedicine | Year: 2013

In this study, hyperpolarized 129Xe MR ventilation and 1H anatomical images were obtained from three subject groups: young healthy volunteers (HVs), subjects with chronic obstructive pulmonary disease (COPD) and age-matched controls (AMCs). Ventilation images were quantified by two methods: an expert reader-based ventilation defect score percentage (VDS%) and a semi-automated segmentation-based ventilation defect percentage (VDP). Reader-based values were assigned by two experienced radiologists and resolved by consensus. In the semi-automated analysis, 1H anatomical images and 129Xe ventilation images were both segmented following registration to obtain the thoracic cavity volume and ventilated volume, respectively, which were then expressed as a ratio to obtain the VDP. Ventilation images were also characterized by generating signal intensity histograms from voxels within the thoracic cavity volume, and heterogeneity was analyzed using the coefficient of variation (CV). The reader-based VDS% correlated strongly with the semi-automatically generated VDP (r=0.97, p<0.0001) and with CV (r=0.82, p<0.0001). Both 129Xe ventilation defect scoring metrics readily separated the three groups from one another and correlated significantly with the forced expiratory volume in 1s (FEV1) (VDS%: r=-0.78, p=0.0002; VDP: r=-0.79, p=0.0003; CV: r=-0.66, p=0.0059) and other pulmonary function tests. In the healthy subject groups (HVs and AMCs), the prevalence of ventilation defects also increased with age (VDS%: r=0.61, p=0.0002; VDP: r=0.63, p=0.0002). Moreover, ventilation histograms and their associated CVs distinguished between subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns. Copyright © 2012 John Wiley & Sons, Ltd.

Khoshnevisan A.,Kings College London | Jauregui-Osoro M.,Kings College London | Shaw K.,Kings College London | Torres J.B.,Kings College London | And 6 more authors.
EJNMMI Research | Year: 2016

Background: [18F]BF4 −, the first 18F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1 GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [18F]BF4 − with higher SA. Methods: A new radiosynthesis of [18F]BF4 − was developed, involving reaction of [18F]F− with boron trifluoride diethyl etherate under anhydrous conditions, guided by 11B and 19F NMR studies of equilibria involving BF4 − and BF3. The SA of the product was determined by ion chromatography. The IC50 of [19F]BF4 − as an inhibitor of [18F]BF4 − uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [19F]BF4 − dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting. Results: An IC50 of 4.8 μΜ was found in vitro indicating a significant risk of in vivo NIS saturation at SA achieved by the isotopic exchange labelling method. In vivo thyroid and salivary gland uptake decreased significantly with [19F]BF4 − doses above ca. 10 μg/kg. The new radiosynthesis gave high radiochemical purity (>99 %) and moderate yield (15 %) and improved SA (>5 GBq/μmol) from a starting activity of only 1.5 GBq. Conclusions: [18F]BF4 − produced at previously reported levels of SA (1 GBq/μmol) can lead to reduced uptake in NIS-expressing tissues in mice. This is much less likely in humans. The synthetic approach described provides an alternative for production of [18F]BF4 − at higher SA with sufficient yield and without need for unusually high starting activity of [18F]fluoride, removing the risk of NIS saturation in vivo even in mice. Trial registration: ISRCTN75827286. © 2016, Khoshnevisan et al.

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