Dr Erik Årstad
UCL/UCLH has recently invested in state-of-the-art facilities for preclinical nuclear imaging (funded by CBRC and HEFCE). The newly build radiochemistry lab has 3 shielded fume hoods (Von Gahlen) and 2 Hot Cells (THC-50, Tema Sinergie). The facilities are equipped with some of the most advanced chemical and analytical equipment available, including analytical radio-HPLCs (Agilent 1200 series with Gabi star radioactivity detectors) and Scintomics automated synthesis modules (HB3). The aim of the research programme is to develop and characterise new tracers for imaging in man. We are currently developing dual optical and nuclear tracers for multiscale imaging with peptides and antibodies, tracers for imaging of neurodegenerative diseases, tracers for imaging of drug resistance and new methods for stem cell tracking.
Examples of previous research
Positron emitters suitable for imaging are short-lived, and the need for rapid automated synthesis, yielding high purity and high-specific activity product, makes production of PET tracers challenging. It is therefore a need for simple, highly efficient and rapid methods for radiolabelling of tracers.
Development of 2-[18F]fluoroethylazide as a labelling agent
Based on the recently develop copper catalysed cyclisation of azides and terminal alkynes, often referred to as ‘click chemistry’, [18F]fluoroethylazide was evaluated as a labelling agent for small molecules and peptides. An advantage of using an azide as the labelling agent is that a number of terminal alkynes are commercially available and can therefore readily be incorporated into biological active compounds.
9 examples ,
61-98% radiochemical yield in step 2
Development of caspase 3/7 selective Isatins for imaging of Apoptosis
Imaging of programmed cell death (apoptosis) is
important in the assessment of therapeutic response in oncology and for
diagnosis in cardiac and neurodegenerative disorders. The executioner
caspases 3 and 7 ultimately effect cellular death, thus providing
selective molecular targets for in vivo quantification of apoptosis. A
small library of isatins modified with fluorinated aromatic groups and
heterocycles was synthesized. A lead compound incorporating
2’-fluoroethyl-1,2,3-triazole was identified with subnanomolar affinity
for caspase 3. “Click labeling” provided the 18F-labeled tracer in 65%
decay-corrected radiochemical yield from 2-[18F]fluoroethylazide. The compound showed high stability in vivo with rapid uptake and elimination in healthy tissues and tumor.
Development and evaluation of tracers for imaging of NMDA receptors function and distribution
N-methyl-D-aspartate (NMDA) receptors are a subtype of ligand-gated ion-channels activated by the excitatory amino acid glutamate. Their expression in the human CNS is widespread and they play a key role in a wide range of biological processes, including neuroplasticity, learning, memory, cognition, neuroprotection, as well as neurodegeneration. In the diseased brain, NMDA dysfunction is linked to a variety of acute and chronic diseases, including stroke, neuropathic pain, schizophrenia and Parkinson’s disease. Development of radiotracers for NMDA receptors is of considerable interest as it will allow studies of normal brain function and may provide new insight into neurological and psychiatric diseases. Tracers targeting the intrachannel PCP site, such as FE CNS (see below) bind selectively to the open NMDA channel and their distribution should therefore reflect channel function. On the other hand, tracers targeting binding sites outside the channel, such as the Ifenprodil binding site, will allow imaging of receptor expression.
Labelling of the NMDA PCP-site ligand [18F]FE CNS
Cartoon of NMDA receptor
Labelling and evaluation of NMDA NR2B selective radioligands
Autoradiography of rat brain sections incubated in vitro with no carrier added [11C]9 (1), under control conditions (1A), in the presence of 100 m M ifenprodil (1B) or in the presence of 100 m M authentic 9 (1C).
Publications and Patents
Publications in peer reviewed journals:
- Robins EG, Zhao YJ, Khan I, Wilson A, Luthra SK, Årstad E (2010). Synthesis and in vitro evaluation of F-18-labelled S-fluoroalkyl diarylguanidines: Novel high-affinity NMDA receptor antagonists for imaging with PET. Bioorg Med Chem Lett. 20(5):1749-1751.
- Schoultz BW, Hjornevik T, Willoch F, Marton J, Noda A, Murakami Y, Miyoshi S, Nishimura S, Årstad E, Drzezga A, Matsunari I, Henriksen G (2010). Evaluation of the kappa-opioid receptor-selective tracer [(11)C]GR103545 in awake rhesus macaques. Eur J Nucl Med Mol Imaging . 37(6): 1174-1180.
- Nguyen QD, Smith G, Glaser M, Perumal M, Årstad E, Aboagye EO (2009). Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide.Proc Natl Acad Sci U S A. 106(38):16375-80.
- De Rosales RTM, Årstad E, Blower P (2009). Nuclear Imaging of Molecular Processes in Cancer. Targeted Oncology. 4(3): 183-197.
- Leyton J, Graham S, Zhao Y, Perumal M, Nguyen QD, Robins E, Årstad E, Aboagye E (2009). [18F]Fluoromethyl-[1,2- 2H 4]-Choline. A novel Radiotracer for Imaging Choline Metabolism in Tumors by Positron Emission Tomography. Cancer Res. 69(19): 7721-7728.
- Glaser M, Årstad E, Luthra SK, Robins EG (2009). Two-step radiosynthesis of [18F]N-succinimidyl-4-fluorobenzoate ([18F]SFB). J. Label Compd. Radiopharm. 52(7-8): 327-330.
- Glaser M, Solbakken M, Turton DR, Pettitt R, Barnett J, Arukwe J, Karlsen H, Cuthbertson A, Luthra SK, Årstad E (2009). Methods for 18F-labeling of RGD peptides: comparison of aminooxy [18F]fluorobenzaldehyde condensation with 'click labeling' using 2-[18F]fluoroethylazide, and S-alkylation with [18F]fluoropropanethiol. Amino Acids, 37(4): 717-724.
- Smith G, Glaser M, Perumal M, Nguyen QD, Shan B, Årstad E, Aboagye EO., Design, synthesis, and biological characterization of a caspase 3/7 selective isatin labeled with 2-[18F]fluoroethylazide (2008).J Med Chem., 51(24), 8057-8067.
- Schoultz BW, Årstad E, Marton J, Willoch F, Drzezga A, Wester HJ, Henriksen G (2008). A New Method for Radiosynthesis of 11C-Labeled Carbamate Groups and its Application for a Highly Efficient Synthesis of the Kappa-Opioid Receptor Tracer [ 11C]GR103545.The Open Medicinal Chemistry Journal, 2(3), 72-74.
- Stone JM, Erlandsson K, Årstad E, Squassante L, Teneggi V, Bressan RA, Krystal JH, Ell PJ, Pilowsky LS (2008). Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study.Psychopharmacology 197(3), 401-408.
- Harriet Teare, Edward G. Robins, Erik Årstad , Sajinder K. Luthra and Veronique Gouverneur (2007). Synthesis and reactivity of [18F]-N-fluorobenzenesulfonimide. Chem. Commun. 23: 2330-2332.
- Matthias Glaser and Erik Årstad (2007), ‘Click Labeling’ with [18F]fluoroethylazide for Positron Emission tomography (PET) . Bioconjugate Chem. , 18(3): 989-993.
- Stone JM, Årstad E, Erlandsson K, Waterhouse RN, Ell PJ, Pilowsky LS (2006), [123I]TPCNE – A novel SPET tracer for the sigma-1 receptor: First human studies and in vivo haloperidol challenge, SYNAPSE, 60(2): 109-107.
- Stone JM, , Erlandsson K, Årstad E, Bressan RA, Squassante L, Teneggi V, Ell PJ, Pilowsky LS (2006), Ketamine displaces the novel NMDA receptor SPET probe [ 123I]CNS-1261 in humans in vivo , Nuclear Medicine and Biology, 33(2), 239-43.
- Årstad E, Gitto R,; Chimirri A, Caruso R, Constanti A, Turton D, Hume SP, Ahmad R, Pilowsky LS, Luthra SK (2006). Closing in on the AMPA receptor: Synthesis and evaluation of 2-acyl-1-(p-chlorophenyl)-6-methoxy-7-[ 11C]methoxy-1,2,3,4-tetrahydroisoquinoline as a potential PET tracer , Bioorganic & Medicinal Chemistry, 14 (14), 4712-4717.
- Zhao Z, Robins E, Turton D, Brady F, Luthra SK, Årstad E (2006), Synthesis and characterization of N-(2-chloro-5-methylthiophenyl)-N'-(3-methylthiophenyl)-N' -[11C]methylguanidine [11C]CNS 5161, a candidate PET tracer for functional imaging of NMDA receptors, Journal of Labeled Compounds and Radiopharmaceuticals, 49 (2), 163-170.
- Årstad, E .; Breistøl, K.; Hoff, P.; Skattebøl, L.; Skretting, A. (2003), Studies on the Synthesis and Biological Properties of n.c.a. [ 125I and 131I] Labelled Arylalkylidenebisphosphonates: Potent Bone-Seekers for Diagnosis and Therapy of Malignant Osseous Lesions . Journal of Medicinal Chemistry , 46(14): 3021-3032.
- Årstad, E .; Barrett, A.G.M.; Tedeschi, L. (2003), ROMPgel-Supported Tris(triphenylphosphine)rhodium(I) chloride: A Selective Hydrogenation Catalyst for Parallel Synthesis, Tetrahedron Letters , 44(13): 2703-2707.
- Årstad, E .; Barrett, A.G.M.; Hopkins, B.T.; Köbberling (2002), ROMPgel-Supported Triphenylphosphine with Potential Application in Parallel Synthesis . Organic Letters , 4(11): 1975-1977.
- Årstad, E .; Skattebøl, L. (2002), Reactions of diethyl mesyl- or tosyloxyphosphonates with diethyl phosphite and base: A method claimed to yield bisphosphonates. Tetrahedron Letters, 43(48): 8711-8712.
Patents and patent applications:
- Isatin derivatives for use as in vivo imaging agents
E Aboagye, G Smith, QD Nguyen, E Arstad, M Glaser, 2010, WO2010026388 (A1)
- Measurement of neural activity
E Arstad, 2010, WO2008152109 (A1)
- Radiolabelling methods
E Arstad, D Turton, 2010, US 2010040545 (A1)
- Radiolabelling methods
M Glaser, E Arstad, 2010, US 2010040550 (A1)
- Chemical methods and apparatus
E Arstad, 2010, US 2010069609 (A1)
- Selective radiolabelling of biomolecules
O Padilla De Jesus, EW Kovacs, M Glaser, E Arstad, FA Syud, 2008 , US 2008161537 (A1) and 2009 , WO2009080561 (A1)
- Radioactive PET agents for imaging CCR5 in vivo
T Storey, J Davis, E Arstad, B Guilbert, A Gaeta, 2009, WO 2008075040 (A2)
- Fluoride drying method
E Arstad, 2009 , US 2009252666 (A1)
- Methods for the purification of radiolabelled compounds E Arstad, 2009 , US 2009312564 (A1)
- Chemical methods and apparatus
E Arstad, C Steel, 2009, CN 101563357 (A)
- Methods for the preparation of [18F]fluoroalkylhalides
E Arstad, 2009, US 2009247793 (A1)
- Tricyclic oxazepines as in vivo imaging compounds
E Arstad, EG Robins, Y Zhao, 2009, US 2009317328 (A1)
- Radiofluorinated compounds and their preparation
E Arstad, M Glaser, 2009, US 2009087379 (A1)
- In vivo imaging compounds
E Arstad, G Henriksen, 2009, US 2009155168 (A1)
- Tetracyclic indole derivatives as in vivo imaging agents and having peripheralbenzodiazepine receptor affinity
E Arstad, I Wilson, SK Luthra, F Brady, B Langstrom, F Karimi, EG Robins, B Shan, 2009, US 2009220420 (A1)
- Radiolabelling methods
E Arstad, M Glaser, 2009, US 2009311177 (A1)
- PET radiotracers
E Arstad, EG Robins, 2008, US 2008292552 (A1)
- Imaging 18F or 11C-labelled alkylthiophenyl guanidines
EG Robins, E Arstad, 2008, WO 2006136846 (A1)
- Purification methods
SK Luthra, F Brady, N Jeffery, E Arstad, A Gibson, D Wynn, A Cuthbertston, M Solbakken, 2010, WO 2005107819 (A2)
- Method for Coating the Internal Surface of a Reaction Vessel
F Brady, N Jefferey, SK Luthra, E Arstad, 2007, US 2007244324 (A1)
- Bis-phosphonate compounds E Arstad, L Skattebol, 2002, US 2002042539 (A1)