Research in our lab includes basic science radiochemistry and translational radiotracer development. Our overall goal is discovery and refinement of tools for molecular imaging, principally by positron emission tomography (PET). PET allows for non-invasive, quantitative and dynamic imaging of biochemical targets, such as receptors or enzymes. A PET radiopharmaceutical can be used to study biochemistry in living systems, diagnose disease or help in development of therapeutics.
The principal isotopes for radiolabeling small molecule PET tracers are carbon-11 and fluorine-18. Due to their short half-lives (20 and 110 minutes, respectively), rapid and efficient chemical reactions are needed to incorporate these into small molecules. Our radiochemistry research currently focuses on preparing new functional groups with carbon-11 by practical methods for radiopharmaceutical production.
Imaging probes for targets implicated in cardiovascular disease, neurological and psychiatric disorders, and oncology are needed to better understand these conditions and develop effective diagnostics and treatments. Our lab uses medicinal chemistry and preclinical imaging to develop radiotracers that will be useful for researchers and practitioners in Ottawa and beyond.
Novel Radiotracers for Inflammation in Atherosclerosis
Currently, it is difficult to detect and accurately predict plaque instability and rupture in atherosclerosis and it is therefore challenging to identify patients in need of treatment before a serious cardiovascular event. One of our goals is to develop a molecular-targeted imaging probe that will be useful for specifically identifying vulnerable plaque burden at high risk for rupture. This probe will allow us to quantitatively measure the density of enzymes that degrade the fibrous cap of atherosclerotic plaques and contribute to their destabilization and increase the likelihood of rupture and thrombus formation. In addition to diagnosis, the probe to be developed could be used to assist in development of therapies targeting these enzymes and to monitor patient response to treatment. This work is funded by the Canadian Institutes of Health Research (PJT148968).
Cardiac Innervation Imaging with PET
Quantitative, high resolution molecular imaging of the cardiac sympathetic nervous system would improve clinical management of associated diseases such as cardiac arrhythmias, congestive heart failure, ischemia, and some cardiac myopathies. In order to take advantage of higher resolution and more easily quantifiable PET imaging, we are validating a fluorine-18 (18F, t1/2 = 109.7 min) radiotracer for imaging myocardial sympathetic innervation for human use. Translational studies are being conducted to develop approaches for quantification of target density. Accompanied by acute toxicity and dosimetry data, these studies will pave the way for clinical evaluation in patients experiencing arrhythmias and HF. This work is supported by an ERLI grant from Heart & Stroke Foundation and its partners.
New Methods with Carbon-11
Carbon-11 (20.3 min half-life) is a versatile isotope for radiotracer development and preclinical imaging, due to its potential to radiolabel any organic compounds and nearly all biomolecules, drugs, and imaging agents. To synthesize imaging agents with carbon-11, chemical transformations need to be performed in rapid succession with high efficiency under strictly controlled conditions to ensure reproducible results and the safety and utility of products. Our research program develops improved chemical methods with carbon-11 and new imaging agents using this isotope. Specifically, we believe that methods for incorporating high oxidation state carbon-11 labels into molecules from its production form as carbon dioxide and similar derivatives such as carbon monoxide and cyanide will greatly expand the synthetic armament for this isotope and directly lead to novel and improved radiopharmaceuticals available to power molecular imaging. As part of this research, students undergo a strong foundation of training in organic chemistry in addition to highly specialized training in radiochemistry with short-lived isotopes and radiopharmaceutical method development, ideally suited for future careers in the medicinal chemistry, radiopharmacy, and imaging sectors.
See current publications list at PubMed.
- Pekošak, A; Rotstein, BH; Collier, TL; Windhorst, AD; Vasdev, N; Poot, AJ. “Stereoselective ¹¹C-Labeling of a "Native" Tetrapeptide Using Asymmetric Phase-Transfer Catalyzed Alkylation Reactions.” Eur. J. Org. Chem. 2017, 1019–1024.
- Yuan, G; Wang, F; Stephenson, NA; Wang, L; Rotstein, BH; Vasdev, N; Tang, P; Liang, SH. “Metal-free 18F Labeling of aryl CF2H via nucleophilic radiofluorination and oxidative C-H activation.” Chem. Commun. 2017, 53, 126–129.
- Hu, K; Patnaik, D; Collier, TL; Lee, KN; Gao, H; Swoyer, M; Rotstein, BH; Krishnan, HS; Liang, SH; Wang, J; Yan, Z; Hooker, JM; Vasdev, N; Haggarty, SJ; Ngai, M-Y. “Development of [18F]maleimide-based glycogen synthase kinase-3β ligands for positron emission tomography imaging.” ACS Med. Chem. Lett. 2017, 8, 287–292.
- Rotstein, BH; Placzek, MS; Krishnan, HS; Pekošak, A; Collier, TL; Wang, C; Liang, SH; Burstein, ES; Hooker, JM; Vasdev, N. “Preclinical PET neuroimaging of [11C]bexarotene.” Mol. Imaging 2016, 15, 1–5. doi: 10.1177/1536012116663054
- Rotstein, BH; Liang, SH; Placzek, MS; Hooker, JM; Gee, AD; Dollé, F; Wilson, AA; Vasdev, N. “11C═O bonds made easily for positron emission tomography.” Chem. Soc. Rev. 2016, 45, 4708–4726.
- Wang, L; Mori, W; Cheng, R; Yui, J; Hatori, A; Ma, L; Zhang, Y; Rotstein, BH; Fujinaga, M; Shimoda, Y; Yamasaki, T; Xie, L; Nagai, Y; Minamimoto, T; Higuchi, M; Vasdev, N; Zhang, M-R; Liang, SH. “Synthesis and preclinical evaluation of sulfonamido-based [11C-carbonyl]-carbamates and ureas for imaging monoacylglycerol lipase.” Theranostics 2016, 6, 1145–1159.
- Rotstein, BH; Wang, L; Liu, RY; Patteson, J; Kwan, EE: Vasdev, N; Liang, SH. “Mechanistic studies and radiofluorination of structurally diverse pharmaceuticals with spirocyclic iodonium(III) ylides.” Chem. Sci. 2016, 7, 4407–4417.
- Wang, L; Yui, J; Wang, Q; Zhang, Y; Mori, W; Shimoda, Y; Fujinaga, M; Kumata, K; Yamasaki, T; Hatori, A; Rotstein, BH; Collier, TL; Ran, C; Vasdev, N; Zhang, M-R; Liang, SH. “Synthesis and preliminary PET imaging studies of a FAAH radiotracer ([11C]MPPO) based on α-ketoheterocyclic scaffold.” ACS Chem. Neurosci. 2016, 7, 109–118.
- Wang, L; Jacobsen, O; Advic, D; Rotstein, BH; Weiss ID; Collier TL; Chen X; Vasdev, N; Liang, SH. “Ortho-stabilized 18F-azide click agents and application in PET imaging of single-stranded DNA aptamer.” Angew. Chem. Int. Ed. 2015, 54, 12777–12781.
- Rotstein, BH; Liang, SH; Belov, VV; Livni, E; Levine, DB; Bonab, AA; Papisov, MI; Perlis, RH; Vasdev, N. “Practical radiosynthesis and preclinical neuroimaging of [11C]isradipine, a calcium channel antagonist.” Molecules 2015, 20, 9551–9559.
- Benjamin Rotstein
Assistant Professor, Scientist
- Rami Al-Haddad
- Ariel Buchler
- Gedaliah Farber
- Moustafa Fouad
- Braeden Mair
- Uzair Sayani
- William Wang