Contact Information
Email: alexey.kostikov [at] mcgill.ca (Alexey Kostikov)
Tel.: 514-398-1503 (office), 514-398-8527 (lab)
Recent Publications: PubMed, Google Scholar
Academic affiliations: Neurology and Neurosurgery, Feindel Brain Imaging Centre
Research group: Neuroimaging and Neuroinformatics
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.
List of selected recent publications (since 2011).
Schirrmacher, R.; Dea, M.; Heiss, W-D.; Kostikov, A.; Funck, T.; Quessy, S.; Bedell, B.; Dancause, N.; Thiel, A. Which Aspects of Stroke Do Animal Models Capture A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1. Cerebrovascular Diseases, 2016, 41, 139-147.
R. Schirrmacher, A. Kostikov, C. Wängler, K. Jurkschat, V. Bernard-Gauthier, E. Schirrmacher, B. Wängler. Silicon Fluoride Acceptors (SIFAs) for peptide and protein labeling with 18F. (in Radiopharmaceuticals for Positron Emission Tomography, Volume 2 in Wiley Series on Radiochemical Syntheses, USA) Ed: P. J. H Scott and B. Hockley, 2015, pp 149-162.
Bernard-Gauthier, V.; Bailey, J. J.; Aliaga A.; Kostikov A.; Rosa-Neto P.; Wuest M.; Brodeur G. M.; Bedell B. J.; Wuest F.; Schirrmacher R. Development of subnanomolar radiofluorinated (2-pyrrolidin-1-yl)imidazo[1,2-b]pyridazine pan-Trk inhibitors as candidate PET imaging probes. MedChemComm, 2015, 6, 2184-2193.
Niedermoser, S.; Wangler, B.; Chin, J.; Kostikov, A.; Wangler, C.; Bernard-Gauthier, V; Schirrmacher, R; Vogler, N.; Soucy, J-P; McEwan, A. J. In Vivo Evaluation of 18F-SiFAlin-Modified TATE: A Potential Challenge for 68Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET. J. Nucl. Med., 2015, 56, 1100-05.
Leuzy, A.; Zimmer, E. R.; Dubois, J.; Pruessner, J.; Cooperman, C.; Soucy, J. P.; Kostikov, A.; Schirmaccher, E.; Désautels, R.; Gauthier, S.; Rosa-Neto, P. In vivo characterization of metabotropic glutamate receptor type 5 abnormalities in behavioral variant FTD Brain Struct. Funct. 2015, 1-16.
Bernard-Gauthier, V.; Aliaga, A.; Aliaga, A.; Boujemeline, M.; Hopewell, R.; Kostikov, A.; Rosa-Neto, P.; Thiel, A.; Schirrmacher, R. 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, 2015, 6, 260-276.
Bernard-Gauthier, V., Wängler, C.; Schirrmacher, E.; Kostikov, A.; Jurkschat, K.; Wängler, B.; Schirrmacher, R. ¹⁸F-labeled silicon-based fluoride acceptors: potential opportunities for novel positron emitting radiopharmaceuticals. Biomed Res Int. 2014, 454503.
Koudih, R.; Kostikov, A.; Kovacevic, M.; Jolly, D.; Bernard-Gauthier, V.; Chin, J.; Jurkschat, K.; Wängler, C.; Wängler, B.; Schirrmacher, R. Automated radiosynthesis of N-succinimidyl 3-(di-tert-butyl[18F]fluorosilyl)benzoate ([18F]SiFB) for peptides and proteins radiolabeling for positron emission tomography. Appl. rad. isot. 2014, 89, 146-150.
Cyr, M.; Parent, M. J.; Mechawar, N.; Rosa-Neto, P.; Soucy, J. P.; Aliaga, A.; Kostikov, A.; Maclaren, D. A.; Clark, S. D.; Bedard, M. A. PET imaging with [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) following selective lesion of cholinergic pedunculopontine tegmental neurons in rat. Nucl. med. biol., 2014, 41, 96-101.
Klan, P.; Solomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.; Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Photoremovable protecting group in chemistry and biology: reaction mechanisms and efficacy. Chem. Rev., 2013, 113, 119-191.
Parent, M. J.; Cyr, M.; Aliaga, A.; Kostikov, A.; Schirrmacher, E.; Soucy, J. P.; Mechawar, N.; Rosa-Neto, P.; Bedard, M. A. Concordance between in vivo and postmortem measurements of cholinergic denervation in rats using PET with [18F]FEOBV and choline acetyltransferase immunochemistry. EJNMMI research, 2013, 3, 70/1-70/6.
Parent, M. J.; Bedard, M. A.; Aliaga, A.; Minuzzi, L.; Mechawar, N.; Soucy, J. P.; Schirrmacher, E.; Kostikov, A.; Gauthier S. G.; Rosa-Neto P. Cholinergic Depletion in Alzheimer's Disease Shown by [18F]FEOBV Autoradiography. International journal of molecular imaging, 2013, 205045/1-205045/7.
Niedermoser, S.; Wängler, C.; Chin, J.; Kostikov, A.; Bartenstein, P.; Jugold, M.; Schirrmacher, E.; Schirrmacher, R.; Wängler, B. Chemical and biological evaluation of new hydrophilic [18F]-SiFA-derivatized somatostatin-analogues. J. Nucl. Med., 2013, 54 (S2), 60.
Hayes, D. J.; Duncan, N. W.; Wiebking, C.; Pietruska, K.; Qin, P.; Lang, S.; Gagnon, J.; Gravel, P.; Verhaeghe, J.; Kostikov, A. P.; Schirrmacher, R.; Reader, A. J.; Doyon, J.; Rainville, P.; Northoff, G. GABAA receptors predict aversion-related brain responses: an fMRI-PET investigation in healthy humans. Neuropsychopharmacology, 2013, 38, 1438-1450.
Wiebking, C.; Duncan, N. W.; Qin, P.; Hayes, D. J.; Lyttelton, O.; Gravel, P.; Verhaeghe, J.; Kostikov, A. P.; Schirrmacher, R.; Reader, A. J.; Bajbouj, M.; Northoff, G. External awareness and GABA-A multimodal imaging study combining fMRI and [18F]flumazenil-PET. Human brain mapping, 2012, 35.
R. Schirrmacher, A. Kostikov, G. Massarweh, M. Kovacevic, C. Wängler, A. Thiel. Synthesis of [18F]Flumazenil ([18F]FZ) (in Radiopharmaceuticals for Positron Emission Tomography, Volume 1 in Wiley Series on Radiochemical Syntheses, USA) Ed: P. J. H Scott and B. Hockley, 2012, pp 111-124.
Qin, P.; Duncan, N. W.; Wiebking, C.; Gravel, P.; Lyttelton, O.; Hayes, D. J.; Verhaeghe, J.; Kostikov, A.; Schirrmacher, R.; Reader, A. J.; Northoff, G. GABA(A) receptors in visual and auditory cortex and neural activity changes during basic visual stimulation. Frontiers in human neuroscience, 2012, 6, 337.
Wängler, B.; Kostikov, A. P.; Niedermoser, S.; Chin, J.; Orchovski, K.; Schirrmacher, E.; Iovkova-Berends, L.; Jurkschat, K.; Wängler, C.; Schirrmacher, R. Protein labeling with the labeling precursor [18F]SiFA-SH for positron emission tomography. Nat. Protoc. 2012, 7, 1964-1969.
Kostikov, A. P.; Chin, J.; Orchovski, K.; Schirrmacher, E.; Niedermoser, S.; Jurkschat, K.; Iovkova-Berends, L.; Wängler, C.; Wängler, B.; Schirrmacher, R. Synthesis of [18F]SiFB: a prosthetic group for direct protein radiolabeling for application in positron emission tomography Nat. Protoc. 2012, 7, 1956-1963.
Wängler, C.; Niedermoser, S.; Chin, J.; Orchovski, K.; Schirrmacher, E.; Jurkschat, K.; Iovkova-Berends, L.; Kostikov, A. P.; Schirrmacher, R.; Wängler, B. One-step 18F-labeling of peptides for positron emission tomography imaging using the SiFA methodology Nat. Protoc. 2012, 7, 1946-1955.
Parent, M.; Bedard, M.-A.; Aliaga, A.; Soucy, J.-P.; Landry St-Pierre, E.; Cyr, M.; Kostikov, A.; Schirrmacher, E.; Massarweh, G.; Rosa-Neto, P. PET imaging of cholinergic deficits in rats using [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) NeuroImage 2012, 62, 555-561.
Wängler, C.; Kostikov, A.; Zhu, J.; Chin, J.; Wängler, B.; Schirrmacher R. Silicon-[18F]fluorine radiochemistry: basics, applications and challenges. Appl. Sci. 2012, 2, 277-302.
Kostikov, A. P.; Chin, J.; Orchowski, K.; Niedermoser, S.; Kovacevic, M. M.; Aliaga, A.; Jurkschat, K.; Wängler, B.; Wängler, C.; Wester, H. J.; Schirrmacher, R. Oxalic acid supported Si-18F-radiofluorination: One-step radiosynthesis of succinimidyl 3-(di-tert-butyl[18F]fluorosilyl)benzoate ([18F]FSiB) for protein labeling. Bioconjugate Chem. 2012, 23, 106-14.
Arumugam, S.; Chin, J.; Schirrmacher, R.; Popik, V. V.; Kostikov, A. P. [18F]Azadibenzocyclooctyne ([18F]ADIBO): A biocompatible radioactive labeling synthon for peptides using catalyst free [3+2] cycloaddition Bioorg. Med. Chem. Lett. 2011, 21, 6987-6991.
Kostikov, A. P.; Iovkova, L.; Chin, J.; Schirrmacher, E.; Waengler, B.; Waengler, C.; Jurkschat, K.; Cosa, G.; Schirrmacher, R. N-(4-(di-tert-butyl[18F]fluorosilyl)benzyl)-2-hydroxy-N,N-dimethylethylammonium bromide ([18F]SiFAN+Br-): A novel lead compound for the development of hydrophilic SiFA-based prosthetic groups for 18F-labeling J. Fluor. Chem. 2011, 132, 27-34.
la Fougere C.; Grant S.; Kostikov A.; Schirrmacher R.; Gravel P.; Schipper H. M; Reader A.; Evans A.; Thiel A. Where in-vivo imaging meets cytoarchitectonics: the relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET NeuroImage 2011, 56, 951-960.
Iovkova-Berends, L.; Wängler, C.; Zöller, T.; Höfner, G.; Wanner, K. T.; Rensch, C.; Bartenstein, P.; Kostikov, A.; Schirrmacher, R.; Jurkschat K.; Wängler, B. t-Bu2SiF-derivatized D2 receptor ligands: the first SiFA-containing small molecule radiotracers for target-specific PET imaging. Molecules, 2011, 16 7458-7479.
