by Benjamin RotsteinImaging glucose utilization is a mainstay and the most well-known application of positron emission tomography (PET) imaging. If one had to choose a single tracer that headlines the technology, surely many would select [18F]2-deoxy-2-fluoro-d-glucose ([18F]FDG). But imaging with [18F]FDG does not reflect the total picture of glucose distribution and metabolism in vivo; it mostly tells us about the facilitated glucose transporters GLUTs, and especially GLUT1, which provides basal glucose supply to almost all tissues. Over the last several years, a group out of University of California Los Angeles (UCLA) has been developing radiotracers for the sodium-glucose linked transporters (SGLTs). Methyl [18F]4-deoxy-4-fluoro-α-D-glucosepyranoside ([18F]Me-4FDG) is also a glucose derivative, but is a poor substrate for the GLUTs and has greater affinity for SGLT1 and SGLT2. Similar to [18F]FDG, [18F]Me-4FDG is effectively trapped intracellularly as it is not a substrate for further downstream metabolism and due to low rate of exit through SGLTs.
Authors: Hiroshi Yamaguchi1, Keiichi Yamashiro2, Yukiko Karuo3, Masaaki Omote3, Kuniharu Imai4,Katsuhiko Kato1 1 Nagoya University Graduate School of Medicine, Department of Integrated Health Sciences, Functional Medical Imaging2 Nagoya University Hospital3 Faculty of Pharmaceutical Sciences, Setsunan University 4 Nagoya University Graduate School of Medicine, Department of Integrated Health Sciences, Medical Imaging Analysis
Authors: Marion TISSERAUD, Sylvain AUVITY, Bertrand KUHNAST, Fabien CAILLE Université Paris-Saclay, Inserm, CNRS, CEA, Laboratoire d’Imagerie Biomédicale Multimodale Paris-Saclay, 91401 Orsay, France Background The p53 protein is essential for the integrity of the cell, stopping cell division in order to repair DNA or by activating apoptosis of altered cells. In several cancers, the protein p53 is deactivated, allowing for the proliferation of tumor. Aims The molecule CP31398 has shown specificity for mutated p53 and is able to restore this protein to suppress cancer cells in vivo.1 Isotopic labelling of CP31398 with carbon-11 would allow for PET imaging of mutated p53 for early detection of aggressive cancers and treatment orientation. Methods For the carbon-11 labelling of CP31398, first, the synthesis of a labelling precursor with a free alcohol will be realized. Once the precursor obtained, the labelling of the free alcohol with [11C]CH3OTf will be realized to obtain the desired radiotracer [11C]CP31398. Results and Conclusion The synthesis of the labelling precursor was carried out using 2-Methyl-4 (3H) -quinazolinone by means of a multi-stage synthesis. The precursor was thus obtained with good yields (20-30%) in 5 steps. First trials of carbon-11 labelling are therefore envisaged with the labelling precursor. References1. Barbara A. Foster; Heather A. Coffey; Michael J. Morin; Farzan Rastinejad, Science, New Series, Vol. 286, No. 5449. (Dec. 24, 1999), pp. 2507-2510.
Authors: Priya Singh, Deepika Singh, Anupriya Adhikari, Anjani Kumar Tiwari* Department of Applied Chemistry & Nuclear Medicine, Babasaheb Bhimrao Ambedkar Univerity, Lucknow, India 226025 Background In search of new ligand for translator protein (TSPO, 18 kDa) which is a known inflammatory and oncological marker and present mainly on outer surface of mitochondria in microglial cells of brain and other peripheral organs such as kidney, lungs, liver, and spleen, a new modified benzoxazolone has been synthesized and compared with Luminescent nanoprobe of TSPO. Aims We have synthesised improved acetamidobenzoxazolone derivatised radioprobe for visualization of 18 kDa TSPO which is able to overcome the limitation of previous generation ligands as well as comparison of sensitivity and specificity with TSPO specific nanoprobes. Methods Computational analysis was performed by Glide, Schrodinger to designated ligand. Reference molecules as well as nano probes were synthesised in wet lab and characterized by different spectroscopic techniques. Mild focal ischemia (MFI) produced by intraluminal occlusion of the middle cerebral artery of SD rats by intraluminal thread model were used for ARG and PET studies. Results and Conclusion In conclusion, we demonstrated that our synthesized PET radioprobe [11C]NeBMP shows radiopharmaceutical profile for imaging of PBR/TSPO expression during neuroinflammation and comparable to nanoprobes . Further opti-mization may lead to a new ligand for clinics for TSPO imaging having minimal impact by TSPO rs6971. References1. Fujinaga M. et al, Development of a 18F-labeled radioligand with improved brain kinetics for positron emission tomography imaging of translocator protein (18 kDa) in ischemic brain and glioma. J Med Chem. 2017, 60, 4047−4061. 2. Tiwari A. K. et al, [18F]FEBMP: Positron Emission Tomography Imaging of TSPO in a Model of Neuroinflammation in Rats, and in vitro Autoradiograms of the Human Brain. Theranostics 2015, 5, 961−969.3. Tiwari A. K. et al, Radiosynthesis and evaluation of acetamidobenzoxazolone based radioligand [11C]N′-MPB for visualization of 18 kDa TSPO in brain. New J. Chem., 2020,44, 7912-7922
Authors: A.V.Ozerskaya1,2, K.V.Belugin2, E.V.Podrezova1, M.S.Larkina3 1. National Research Tomsk Polytechnic University, 30, Lenin Avenue, Tomsk 634050, Russia2. Federal Siberian Research Clinical Centre under the Federal Medical Biological Agency, 26 Kolomenskaya Street, Krasnoyarsk, 660037, Russia3. Siberian State Medical University, 2 Moskovsky trakt, Tomsk, 634050, Russia
Authors: Muzzioli R1, Paolillo V2, Zacharias Millward N3, Gammon ST1, Pisaneschi F1, Piwnica-Worms D1 1Department of Cancer System Imaging, 2Center for Advanced Biomedical Imaging, 3Department of Urology; The University of Texas MD Anderson Cancer Center, Houston,77034, TX, USA Background Three PET tracers, among those synthesized at MD Anderson Cancer Center, were selected for a comparative analysis of radiolabeling efficiency using two different approaches: a classic “reactor” automated system or a microfluidic system. The tracers selected were: [18F]fluoroazomycin arabinoside ([18F]FAZA), 4-[18F]fluoronaphthol ([18F]4FN) and -4-[18F]fluoroglutamine ([18F]FGln). Aims The study aims to compare the radiolabeling conditions of three different PET tracers using an automated synthesis module (GE-Tracerlab-FX for [18F]FAZA and [18F]4FN, and GE-Tracerlab-FX2N for [18F]FGln) and a microfluidic system (Avion-NanoTek). The goal is to have a work-flow that allows screening in microfluidics and scale-up on a classic reactor. Methods The synthesis of [18F]4FN uses a copper-mediated radiofluorination/deprotection of an aryl boronic esters precursor. The radiolabeling reaction for the synthesis of [18F]FGln and [18F]FAZA is based on a nucleophilic substitution (SN2), starting from a precursor that bears a tosylate moiety as leaving group. Results and Conclusion All the PET tracers were synthetized on GE Tracerlab. [18F]4FN was obtained in 6.8±2.5% (n=22) activity yield, [18F]FGln in 8.5±2.9 % (n=7) radioactivity yield and [18F]FAZA in a 28.1±3.8 % (n=37) activity yield, with> 99% radiochemical purity and high molar activity. Radiolabeling of the tracers on the NanoTek is underway. References1. Tredwell, M., et al., A General Copper-Mediated Nucleophilic 18F Fluorination of Arenes. Angewandte Chem. Int. Edit., 2014. 53(30): p. 7751-7755.2. Zhang, X., et al., Automated synthesis of [(18)F](2S,4R)-4-fluoroglutamine on a GE TRACERlab FX-N Pro module. Appl Radiat Isot, 2016. 112: p. 110-4.3. Reischl, G., et al., Preparation of the hypoxia imaging PET tracer [18F]FAZA: reaction parameters and automation. Appl. Radiat. Isot., 2005. 62(6): p. 897-901.
Authors: K. Makrypidi, C. Kiritsis, I. Roupa, A. Chiotellis, M. Papadopoulos, I. Pirmettis NCSR “Demokritos”, NKUA-Pharmacy Department, Greece Background 2-18F-fluoro-deoxyglucose ([18F]FDG) is the most applied radiopharmaceutical for glucose metabolism imaging. It has been used for the in-situ labelling of various bioactive amines employing the Maillard reaction. As [18F]FDG lacks the hydroxyl group at the 2nd position, it undergoes the Maillard reaction without forming the classical Amadori product1. Aims Aiming at the development of PET tracers for imaging Epidermal Growth Factor Receptor (EGFR), herein we report on the coupling and radiolabelling of the EGFR tyrosine kinase inhibitor, 6-amino-4-[(3-bromophenyl)amino]quinazoline with FDG. Methods The 6-amino-4-[(3-bromophenyl)amino]quinazoline and FDG were synthesized based on existing literature2,3. The Maillard reaction, meaning the amine coupling to FDG, will be performed and the expected fluorine derivative will be characterized. The [18F]FDG derivative will be prepared and identified with co-injection in HPLC, using its non-radioactive analogue as a reference. Results and Conclusion The amine precursor, bearing an aromatic amine at 6th position, was obtained in four steps using the 4-hydroxyquinazoline, as starting material. The synthesis of 6-amino-4-[(3-bromophenyl)amino]quinazoline was performed in overall high yield while FDG was synthesized in rather low yield. The results from amine coupling and [18F]FDG radiolabeling will be presented. References1. Baranwal A. et al. 18F-Fluorodeoxyglycosylamines: Maillard reaction of 18F-fluorodeoxyglucose with biological amines. J Labelled Comp Radiopharm. 2014; 57(2): 86-912. Fernandes C. et al. Rhenium and technetium complexes bearing quinazoline derivatives: progress towards a 99mTc biomarker for EGFR-TK imaging. Dalton Trans. 2008; 3215-32253. Kováč P. A short synthesis of 2-deoxy-2-fluoro-D-glucose. Carbohydrate Research. 1986;153: 168-170
Authors: Federico Luzi, Antony Gee, Salvatore Bongarzone King’s College London Background Formamides are common motifs of biologically-active compounds (e.g. formoterol, octotiamine, fursaltiamine etc)1 and are frequently employed as intermediates to yield, for example, benzimidazoles.2 A rapid, simple and reliable route to [carbonyl-11C]formamides would enable access to this important class of compounds as in vivo PET imaging agents. Aims We report the rapid, one-pot 11C-formylation of amines via the reduction of [11C]isocyanate intermediates formed directly from cyclotron-produced [11C]CO2. The method was applied to the radiolabelling of a small library of formamides and the chemotactic molecule formyl methionine.
Authors: Pardeep Kumar1, Raman Kumar Joshi1, Chandana Nagaraj1, N. Sridhar Goud1, Naren P Rao2 Department of Neuroimaging and Interventional Radiology1, Psychiatry2 Background Fluorine-18 [18F]flumazenil (FMZ) has been used for the assessment of the gamma amino butyric acid (GABA) receptors by positron emission tomography (PET). [11C] or [18F]flumazenil have been used for PET imaging of various types of neurodisorders. Aims To standardize and synthesize [18F]flumazenil using various combinations of the solid phase cartridges in order to minimize the loss of radiochemical yield during purification. Methods The precursor nitormazenil was procured from Syncom BV, Netherlands. The radio-fluorination was standardized for various parameters like temperature (130-160°C), precursor concentration (3-5 mg), various combination of SPE cartridges (HLB, tC18, C18 and alumina) and final product eluted by using 2.0 mL of 20% ethanol/ phosphate buffer (pH-4.0). The radiochemical purity was calculated by using Radio-HPLC. Results and Conclusion The combination of C18 and alumina cartridges gave the highest yield (15 ± 2 %) as compare to 1-2% by other two combination. The radiochemical purity was 95 ± 3 % with retention time at 15.4 ± 0.3 min (n = 10). [18F]flumazenil was synthesized with higher radiochemical purity and a simple automated method has been developed for the clinical use.
Authors: Thines Kanagasundaram1,2,3, Sven Stadlbauer1, Carsten Sven Kramer3, Klaus Kopka1,4 1Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, GERMANY2Heidelberg University, Faculty of Chemistry and Earth Sciences, Heidelberg, GERMANY3German Cancer Research Center, Heidelberg, GERMANY 4Technical University Dresden, Faculty of Chemistry and Food Chemistry, Dresden, GERMANY
Authors: Francesca Goudoua,b,c, Virginie Hourtaneb, Nicolas Masseb, Yahya Cisseb, Abdul Karim Haji Dheerec and Antony Geec a SYNBIOLAB – Actualis Jarry, 44 rue Henry Becquerel Jarry 97122 Baie-Mahault – Guadeloupe.b PMB Head office – France Route des Michels CD56, La Corneirelle 13790 Peynier – France. c School of Imaging Sciences and Biomedical Engineering, King’s College London, London, SE1 7EH, UK.
Authors: Biti, A., Fraguas-Sánchez, A.I., & Sarparanta, M. University of Helsinki Background Adoptive cell therapy is a promising mode of cancer therapy employing tumor infiltrating lymphocytes (TILs) with a limited success to hematologic cancers and melanoma.1 Molecular imaging strategies based on bioorthogonal chemistry and metabolic glycoengineering for in vivo tracking of TILs provide advantages compared to conventional techniques.2 Aims The aim of this study is to develop a new radiolabeling method for TILs without impairment of their antitumor and homing properties by using a Staudinger ligation between a perfluoroaryl azide tag3 on the surface of murine OT-I lymphocytes installed by metabolic glycoengineering and novel fluorine-18 radiolabeled phosphine reagents. Methods The PFAA-modified D-mannosamine is synthesized according to a reported procedure. The phosphine reagents present a linker and the NODAGA radiochelator and are synthesized by using common organic reactions. The radiolabeling with [18F]aluminum fluoride (AlF) requires in situ synthesis of [18F]AlF starting from saline-eluted [18F]fluoride ion and aluminum chloride (AlCl3). Results and Conclusion This labeling method eliminates the drying step needed for most [18F]F− labeling methods. Furthermore, Al18F complexes are hydrophilic and can be used for the radiolabeling of sensitive targets such as cells in aqueous systems. This could be a method towards the radiolabeling of TILs without genetic manipulation. References 1. Schietinger, A., et al., Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis. Immunity, 2016. 45(2): p. 389-401.2. Rossin, R., et al., Diels–Alder Reaction for Tumor Pretargeting: In Vivo Chemistry Can Boost Tumor Radiation Dose Compared with Directly Labeled Antibody. Journal of Nuclear Medicine, 2013. 54(11): p. 1989-1995.3. Sundhoro, M., et al., Perfluoroaryl Azide Staudinger Reaction: A Fast and Bioorthogonal Reaction. Angewandte Chemie International Edition, 2017. 56(40): p. 12117-12121.