Alexey Kostikov - profile revision

Positron Emission Tomography (PET) is a non-invasive in vivo imaging modality which relies on detecting radioactive decay of the isotope attached to a biologically active molecule, such as sugar, peptide, receptor ligand etc. PET is applied in clinical and basic research in all major medical fields including cardiology, neurology and oncology: it offers unique biological specificity, sensitivity, tissue penetration depth and precise dynamic quantification. PET is especially powerful in receptor studies of e.g. translocator protein (TSPO), glutamate (mGluR5), somatostatin and estrogen receptors, GABAergic, dopamine and serotonin neurotransmission systems. Recently, PET has been extensively used in detection of abnormal accumulation of misfolded proteins, such as β-amyloid and tau, associated with a variety of neurodegenerative diseases. My research program in PET radiochemistry is focused on optimization of the radiolabeling procedures to incorporate the radioactive isotope in small organic molecules as well as larger biorelevant molecules, development of novel radiopharmaceuticals and their applications in PET imaging.

Novel radiolabeling techniques

Solid phase supported radiolabeling with Fluorine-18 and Carbon-11. Incorporation of isotopes F-18 and C-11 into the molecules of PET radiotracers predominantly relies on reaction of primary labeling agents (18F- and [11C]MeI, respectively) with non-radioactive precursors in common organic solvent solution. We have been developing a new solid support radiolabeling procedure which takes advantage of the polymer resin reversely binding anions, such as 18F-, making them very reactive towards radiolabeling. Solution of the precursor is passed through the resin with absorbed 18F- anion and radiolabeling occurs on the resin. In the case of [11C]methylation, the precursor is trapped on the resin, the gaseous [11C]MeI or [11C]MeOTf is passed through and the resulting radiotracer is washed out with an aqueous solution while impurities and unreacted starting materials remain trapped on the resin. This technique significantly simplifies technical effort involved in production of every batch of radiopharmaceutical, improves reliability of the synthesis and shortens the synthesis time, affording higher yields of the labeled compound. We have already showed the applicability of this approach on some model compounds and are now applying this technique for radiolabeling of clinically relevant radiotracers.

Copper free click chemistry for radiolabeling of peptides and proteins

Organic macromolecules, such as proteins and peptides, are often structurally incompatible with the harsh reaction conditions typically required to incorporate positron-emitting radioisotopes. Therefore, radiolabeling of these compounds relies on using so-called prosthetic groups, small organic molecules which are first radiolabeled and then conjugated to the fragile substrate under mild conditions. Radiolabeled peptides are of major importance for tumor imaging in diagnostic nuclear medicine oncology: radiochemical methods to label these compounds quickly and efficiently are highly sought after. We have developed very promising approach towards peptide radiolabeling which relies on the recently discovered strain-promoted acetylene-azide cycloaddition (SPAAC) copper free click reaction. In this method a cyclooctyne containing strained triple bond (1) is first 18F-fluorinated and the resulting [18F]ADIBO synthon (2) is reacted with the azide-modified peptide. We are now looking to modify this prosthetic group in order to improve aqueous solubility and the rate of radiolabeling.

Development of new radiotracers for neuroreceptor imaging

Neurotrophins – nerve growth factor NGF, brain-derived neurotrophic factor BDNF, NT3 and NT4/5, as well as their endogenous pro forms – is a family of growth factors, critically involved in the regulation of neuronal functions. They are signalling through a three distinct types of receptors: tropomyosin receptor kinase family (TrkA/B/C), p75 neurotrophin receptor (p75NTR), and sortilin, a member of a Vps10p-domain receptor family. The cellular response (i.e. survival, differentiation or death) depends on the cell line, operating ligand and relative coexpression of these receptors. Aberrant regulation of all of these receptors in CNS is implicated in a variety of neurodegenerative diseases, including Alzheimer’s, Parkinson’s etc. We are developing novel PET radiotracers for p75NTR and sortilin receptor imaging and are involved in collaboration on Trk PET tracers development.

Multitracer imaging of Chronic Traumatic Encephalopathy

Traumatic brain injury (TBI) affects an estimated 160,000 Canadians each year and over a million of Canadians suffer from long-term effect of TBI according to Brain Injury Canada. In a long term, repetitive acute brain traumas (including concussions) trigger a neurodegenerative chronic traumatic encephalopathy (CTE), which primarily affects professional athletes in contact sports (football, rugby, ice hockey, etc.) and military personnel. Early detection of CTE would accelerate the development and clinical trials of experimental therapeutic interventions and allow for monitoring of the disease progression; however, currently clinical diagnosis of CTE remains elusive. PET provides a unique opportunity to independently observe three biomarkers implicated in chronic phase of TBI and CTE in vivo: neuroinflammation, neurofibrillary tangles of misfolded tau protein, and senile plaques of β-amyloid protein. We are developing a PET imaging study to identify reliable biomarkers of CTE using multiple tracers routinely produced in our radiochemistry facility at the MNI.

Selected publications

    • Bernard-Gauthier, V., Mossine, A. V., Mahringer, A., Aliaga, A., Bailey, J. J., Shao, X., . . . Schirrmacher, R. (2018). Identification of [(18)F]TRACK, a fluorine-18-labeled tropomyosin receptor kinase (trk) inhibitor for PET imaging. Journal of Medicinal Chemistry, 61(4), 1737-1743. 10.1021/acs.jmedchem.7b01607 Link to item
    • Boudjemeline, M., McNitt, C. D., Singleton, T. A., Popik, V. V., & Kostikov, A. P. (2018). (18)F]ODIBO: A prosthetic group for bioorthogonal radiolabeling of macromolecules via strain-promoted alkyne-azide cycloaddition. Organic & Biomolecular Chemistry, 16(3), 363-366. 10.1039/c7ob02532g Link to item
    • Bernard-Gauthier, V., Bailey, J. J., Mossine, A. V., Lindner, S., Vomacka, L., Aliaga, A., . . . Scott, P. J. H. (2017). A kinome-wide selective radiolabeled TrkB/C inhibitor for in vitro and in vivo neuroimaging: Synthesis, preclinical evaluation, and first-in-human. Journal of Medicinal Chemistry, 60(16), 6897-6910. 10.1021/acs.jmedchem.7b00396 Link to item
    • Boudjemeline, M., Hopewell, R., Rochon, P. L., Jolly, D., Hammami, I., Villeneuve, S., & Kostikov, A. (2017). Highly efficient solid phase supported radiosynthesis of [(11) C]PiB using tC18 cartridge as a “3-in-1” production entity. Journal of Labelled Compounds & Radiopharmaceuticals, 60(14), 632-638. 10.1002/jlcr.3569 Link to item
    • Jolly, D., Hopewell, R., Kovacevic, M., Li, Q. Y., Soucy, J. P., & Kostikov, A. (2017). Development of “[(11)C]kits” for a fast, efficient and reliable production of carbon-11 labeled radiopharmaceuticals for positron emission tomography. Applied Radiation and Isotopes : Including Data, Instrumentation and Methods for use in Agriculture, Industry and Medicine, 121, 76-81. S0969-8043(16)30588-7 Link to item
    • Parent, M. J., Zimmer, E. R., Shin, M., Kang, M. S., Fonov, V. S., Mathieu, A., . . . Rosa-Neto, P. (2017). Multimodal imaging in rat model recapitulates alzheimer’s disease biomarkers abnormalities. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 37(50), 12263-12271. 10.1523/JNEUROSCI.1346-17.2017 Link to item
    • Gibon, J., Kang, M. S., Aliaga, A., Sharif, B., Rosa-Neto, P., Seguela, P., . . . Kostikov, A. (2016). Towards the PET radiotracer for p75 neurotrophin receptor: [(11)C]LM11A-24 shows biological activity in vitro, but unfavorable ex vivo and in vivo profile. Bioorganic & Medicinal Chemistry, 24(19), 4759-4765. S0968-0896(16)30627-7 Link to item
    • Leuzy, A., Zimmer, E. R., Dubois, J., Pruessner, J., Cooperman, C., Soucy, J. P., . . . Rosa-Neto, P. (2016). In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD. Brain Structure & Function, 221(3), 1387-1402. 10.1007/s00429-014-0978-3 Link to item
    • Schirrmacher, R., Dea, M., Heiss, W. D., Kostikov, A., Funck, T., Quessy, S., . . . Thiel, A. (2016). Which aspects of stroke do animal models capture? A multitracer micro-PET study of focal ischemia with endothelin-1. Cerebrovascular Diseases (Basel, Switzerland), 41(3-4), 139-147. 10.1159/000442997 Link to item
    • Bernard-Gauthier, V., Aliaga, A., Aliaga, A., Boudjemeline, M., Hopewell, R., Kostikov, A., . . . Schirrmacher, R. (2015). Syntheses and evaluation of carbon-11- and fluorine-18-radiolabeled pan-tropomyosin receptor kinase (trk) inhibitors: Exploration of the 4-aza-2-oxindole scaffold as trk PET imaging agents. ACS Chemical Neuroscience, 6(2), 260-276. 10.1021/cn500193f Link to item
    • Niedermoser, S., Chin, J., Wangler, C., Kostikov, A., Bernard-Gauthier, V., Vogler, N., . . . Wangler, B. (2015). In vivo evaluation of (1)(8)F-SiFAlin-modified TATE: A potential challenge for (6)(8)ga-DOTATATE, the clinical gold standard for somatostatin receptor imaging with PET. Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine, 56(7), 1100-1105. 10.2967/jnumed.114.149583 Link to item
    • Bernard-Gauthier, V., Wangler, C., Schirrmacher, E., Kostikov, A., Jurkschat, K., Wangler, B., & Schirrmacher, R. (2014). (1)(8)F-labeled silicon-based fluoride acceptors: Potential opportunities for novel positron emitting radiopharmaceuticals. BioMed Research International, 2014, 454503. 10.1155/2014/454503 Link to item
    • Cyr, M., Parent, M. J., Mechawar, N., Rosa-Neto, P., Soucy, J. P., Aliaga, A., . . . Bedard, M. A. (2014). PET imaging with [(1)(8)F]fluoroethoxybenzovesamicol ([(1)(8)F]FEOBV) following selective lesion of cholinergic pedunculopontine tegmental neurons in rat. Nuclear Medicine and Biology, 41(1), 96-101. 10.1016/j.nucmedbio.2013.10.004 Link to item
    • Wiebking, C., Duncan, N. W., Qin, P., Hayes, D. J., Lyttelton, O., Gravel, P., . . . Northoff, G. (2014). External awareness and GABA–a multimodal imaging study combining fMRI and [18F]flumazenil-PET. Human Brain Mapping, 35(1), 173-184. 10.1002/hbm.22166 Link to item
    • Hayes, D. J., Duncan, N. W., Wiebking, C., Pietruska, K., Qin, P., Lang, S., . . . Northoff, G. (2013). GABAA receptors predict aversion-related brain responses: An fMRI-PET investigation in healthy humans. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 38(8), 1438-1450. 10.1038/npp.2013.40 Link to item
    • Klan, P., Solomek, T., Bochet, C. G., Blanc, A., Givens, R., Rubina, M., . . . Wirz, J. (2013). Photoremovable protecting groups in chemistry and biology: Reaction mechanisms and efficacy. Chemical Reviews, 113(1), 119-191. 10.1021/cr300177k Link to item
    • Parent, M. J., Bedard, M. A., Aliaga, A., Minuzzi, L., Mechawar, N., Soucy, J. P., . . . Rosa-Neto, P. (2013). Cholinergic depletion in alzheimer’s disease shown by [ (18) F]FEOBV autoradiography. International Journal of Molecular Imaging, 2013, 205045. 10.1155/2013/205045 Link to item
    • Parent, M. J., Cyr, M., Aliaga, A., Kostikov, A., Schirrmacher, E., Soucy, J. P., . . . Bedard, M. A. (2013). Concordance between in vivo and postmortem measurements of cholinergic denervation in rats using PET with [18F]FEOBV and choline acetyltransferase immunochemistry. EJNMMI Research, 3(1), 70-219X-3-70. 10.1186/2191-219X-3-70 Link to item
    • Kostikov, A. P., Chin, J., Orchowski, K., Niedermoser, S., Kovacevic, M. M., Aliaga, A., . . . Schirrmacher, R. (2012). Oxalic acid supported si-18F-radiofluorination: One-step radiosynthesis of N-succinimidyl 3-(di-tert-butyl[18F]fluorosilyl)benzoate ([18F]SiFB) for protein labeling. Bioconjugate Chemistry, 23(1), 106-114. 10.1021/bc200525x Link to item
    • Kostikov, A. P., Chin, J., Orchowski, K., Schirrmacher, E., Niedermoser, S., Jurkschat, K., . . . Schirrmacher, R. (2012). Synthesis of [(18)F]SiFB: A prosthetic group for direct protein radiolabeling for application in positron emission tomography. Nature Protocols, 7(11), 1956-1963. 10.1038/nprot.2012.110 Link to item
    • Parent, M., Bedard, M. A., Aliaga, A., Soucy, J. P., Landry St-Pierre, E., Cyr, M., . . . Rosa-Neto, P. (2012). PET imaging of cholinergic deficits in rats using [18F]fluoroethoxybenzovesamicol ([18F]FEOBV). Neuroimage, 62(1), 555-561. 10.1016/j.neuroimage.2012.04.032 Link to item
    • Qin, P., Duncan, N. W., Wiebking, C., Gravel, P., Lyttelton, O., Hayes, D. J., . . . Northoff, G. (2012). GABA(A) receptors in visual and auditory cortex and neural activity changes during basic visual stimulation. Frontiers in Human Neuroscience, 6, 337. 10.3389/fnhum.2012.00337 Link to item
    • Wangler, B., Kostikov, A. P., Niedermoser, S., Chin, J., Orchowski, K., Schirrmacher, E., . . . Schirrmacher, R. (2012). Protein labeling with the labeling precursor [(18)F]SiFA-SH for positron emission tomography. Nature Protocols, 7(11), 1964-1969. 10.1038/nprot.2012.111 Link to item
    • Wangler, C., Niedermoser, S., Chin, J., Orchowski, K., Schirrmacher, E., Jurkschat, K., . . . Wangler, B. (2012). One-step (18)F-labeling of peptides for positron emission tomography imaging using the SiFA methodology. Nature Protocols, 7(11), 1946-1955. 10.1038/nprot.2012.109 Link to item
    • Arumugam, S., Chin, J., Schirrmacher, R., Popik, V. V., & Kostikov, A. P. (2011). 18F]azadibenzocyclooctyne ([18F]ADIBO): A biocompatible radioactive labeling synthon for peptides using catalyst free [3+2] cycloaddition. Bioorganic & Medicinal Chemistry Letters, 21(23), 6987-6991. 10.1016/j.bmcl.2011.09.126 Link to item
    • Iovkova-Berends, L., Wangler, C., Zoller, T., Hofner, G., Wanner, K. T., Rensch, C., . . . Wangler, B. (2011). t-Bu2SiF-derivatized D2-receptor ligands: The first SiFA-containing small molecule radiotracers for target-specific PET-imaging. Molecules (Basel, Switzerland), 16(9), 7458-7479. 10.3390/molecules16097458 Link to item
    • la Fougere, C., Grant, S., Kostikov, A., Schirrmacher, R., Gravel, P., Schipper, H. M., . . . Thiel, A. (2011). Where in-vivo imaging meets cytoarchitectonics: The relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET. Neuroimage, 56(3), 951-960. 10.1016/j.neuroimage.2010.11.015 Link to item
    • Baldwin, J. E., & Kostikov, A. P. (2010). On the stereochemical characteristic of the thermal reactions of vinylcyclobutane. The Journal of Organic Chemistry, 75(9), 2767-2775. 10.1021/jo1000675 Link to item
    • Baldwin, J. E., Kiemle, D. J., & Kostikov, A. P. (2009). Quantitative analyses of mixtures of 2-deuterio-1-vinylcyclobutanes. The Journal of Organic Chemistry, 74(20), 7866-7872. 10.1021/jo901663v Link to item
    • Baldwin, J. E., Kiemle, D. J., & Kostikov, A. P. (2009). Quantitative analyses of stereoisomeric 3,4-d2-cyclohexenes in the presence of 3,6-d2-cyclohexenes. The Journal of Organic Chemistry, 74(10), 3866-3874. 10.1021/jo900430w Link to item
    • Kostikov, A. P., Malashikhina, N., & Popik, V. V. (2009). Caging of carbonyl compounds as photolabile (2,5-dihydroxyphenyl)ethylene glycol acetals. The Journal of Organic Chemistry, 74(4), 1802-1804. 10.1021/jo802612f Link to item
    • Kostikov, A. P., & Popik, V. V. (2008). Photolabile protection of 1,2- and 1,3-diols with salicylaldehyde derivatives. Organic Letters, 10(22), 5277-5280. 10.1021/ol802141g Link to item
    • Kostikov, A. P., & Popik, V. V. (2007). 2,5-dihydroxybenzyl and (1,4-dihydroxy-2-naphthyl)methyl, novel reductively armed photocages for the hydroxyl moiety. The Journal of Organic Chemistry, 72(24), 9190-9194. 10.1021/jo701426j Link to item

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