Electrophilic Aromatic Synthesis of Radioiodinated Aripiprazole: Experimental and DFT Investigations

Author(s): Moustapha E. Moustapha, Mohammed H. Geesi, Zeinab R. Farag, El Hassane Anouar*

Journal Name: Current Organic Synthesis

Volume 17 , Issue 4 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Aripiprazole is a quinolinone derivative. It shows a high affinity for neurotransmitters dopamine and serotonin receptors, which can overcome the blood-brain barrier (BBB) to reach the central nervous system (CNS) to exert therapeutic effects. Its radioiodination may lead to high radiochemical yield and improved its affinity. Aripiprazole radioiodination is an aromatic electrophilic substitution.

Objective: Herein, we investigate the favorable atom site of the aromatic electrophilic substitution of aripiprazole by calculating the Fukui indices of heavy atoms and ESP charges of the parent molecule.

Methods: The calculations have been carried out at the B3LYP/LanL2DZ level of theory. The iodinated aripiprazole structure is confirmed by comparing the experimental and the predicted 1H NMR chemical shifts of the parent molecule and its iodinated forms.

Results: Finally, the electronic properties of aripiprazole and its iodinated form were calculated at the same level of theory. Nucleophilic Fukui indices and ESP charges calculations confirm that C8 is the most favorable site of the electrophilic substitution. The calculated electronic properties (e.g, gap energy, electron affinity, and electronegativity) of aripiprazole and its iodinated form reveal the higher reactivity of iodinated aripiprazole compared with aripiprazole.

Conclusion: This may explain the higher affinity of iodinated aripiprazole and the increase of its radiochemical yield.

Keywords: Aripiprazole, oxidative iodination, electrophilic substitution, fukui indices, GIAO, DFT.

[1]
Wunder, A.; Klohs, J.; Dirnagl, U. Non-invasive visualization of CNS inflammation with nuclear and optical imaging. Neuroscience, 2009, 158(3), 1161-1173.
[http://dx.doi.org/10.1016/j.neuroscience.2008.10.005] [PMID: 18983900]
[2]
Camargo, E.E. Brain SPECT in neurology and psychiatry. J. Nucl. Med., 2001, 42(4), 611-623.
[PMID: 11337551]
[3]
Ametamey, S.M.; Schubiger, P. PET radiopharmaceuticals for neuroreceptor imaging. Nucl. Sci. Tech., 2006, 17(3), 143-147.
[http://dx.doi.org/10.1016/S1001-8042(06)60028-6]
[4]
Wernick, M.N.; Aarsvold, J.N. Emission tomography: The fundamentals of PET and SPECT; Elsevier, 2004.
[5]
Catafau, A.M.; Suarez, M.; Bullich, S.; Llop, J.; Nucci, G.; Gunn, R.N.; Brittain, C.; Laruelle, M. Within-subject comparison of striatal D2 receptor occupancy measurements using [123I]IBZM SPECT and [11C]Raclopride PET. Neuroimage, 2009, 46(2), 447-458.
[http://dx.doi.org/10.1016/j.neuroimage.2009.02.005] [PMID: 19233294]
[6]
Kung, H.F. Radiopharmaceuticals for single-photon emission computed tomography brain imaging. Semin. Nucl. Med., 2003, 33(1), 2-13.
[http://dx.doi.org/10.1053/snuc.2003.127296] [PMID: 12605353]
[7]
la Fougère, C.; Rominger, A.; Förster, S.; Geisler, J.; Bartenstein, P. PET and SPECT in epilepsy: A critical review. Epilepsy Behav., 2009, 15(1), 50-55.
[http://dx.doi.org/10.1016/j.yebeh.2009.02.025] [PMID: 19236949]
[8]
Verhoeff, N.P.L. Radiotracer imaging of dopaminergic transmission in neuropsychiatric disorders. Psychopharmacology (Berl.), 1999, 147(3), 217-249.
[http://dx.doi.org/10.1007/s002130051163] [PMID: 10639681]
[9]
Rickards, H. Functional neuroimaging in Tourette syndrome. J. Psychosom. Res., 2009, 67(6), 575-584.
[http://dx.doi.org/10.1016/j.jpsychores.2009.07.024] [PMID: 19913661]
[10]
Heinz, A.; Jones, D.W.; Raedler, T.; Coppola, R.; Knable, M.B.; Weinberger, D.R. Neuropharmacological studies with SPECT in neuropsychiatric disorders. Nucl. Med. Biol., 2000, 27(7), 677-682.
[http://dx.doi.org/10.1016/S0969-8051(00)00135-9] [PMID: 11091111]
[11]
Pardridge, W.M. Blood-brain barrier biology and methodology. J. Neurovirol., 1999, 5(6), 556-569.
[http://dx.doi.org/10.3109/13550289909021285] [PMID: 10602397]
[12]
Haines, B.E.; Yu, J-Q.; Musaev, D.G. The mechanism of directed Ni(ii)-catalyzed C-H iodination with molecular iodine. Chem. Sci. (Camb.), 2017, 9(5), 1144-1154.
[http://dx.doi.org/10.1039/C7SC04604A] [PMID: 29675159]
[13]
Sloan, N.L.; Sutherland, A. Recent advances in transition-metal-catalyzed iodination of arenes. Synthesis, 2016, 48(18), 2969-2980.
[http://dx.doi.org/10.1055/s-0035-1562439]
[14]
Adam, M.J.; Wilbur, D.S. Radiohalogens for imaging and therapy. Chem. Soc. Rev., 2005, 34(2), 153-163.
[http://dx.doi.org/10.1039/b313872k] [PMID: 15672179]
[15]
Neumeyer, J.L.; Wang, S.; Milius, R.A.; Baldwin, R.M.; Zea-Ponce, Y.; Hoffer, P.B.; Sybirska, E.; Al-Tikriti, M.; Charney, D.S. [123I]-2. beta.-carbomethoxy-3. beta.-(4-iodophenyl) tropane: High-affinity SPECT (single photon emission computed tomography) radiotracer of monoamine reuptake sites in brain. J. Med. Chem., 1991, 34(10), 3144-3146.
[http://dx.doi.org/10.1021/jm00114a027] [PMID: 1920365]
[16]
Adam, M.J.; Ponce, Y.Z.; Berry, J.M. Synthesis of L‐6‐[123I] iodo‐m‐tyrosine a potential spect brain imaging agent. J. Labelled Comp. Radiopharm., 1990, 28(9), 1065-1072.
[http://dx.doi.org/10.1002/jlcr.2580280911]
[17]
Moustapha, M.; Motaleb, M.; Ibrahim, I.; Moustafa, M. Oxidative radioiodination of aripiprazole by chloramine-T as a route to a potential brain imaging agent: A mechanistic approach. Radiochemistry, 2013, 55(1), 116-122.
[http://dx.doi.org/10.1134/S1066362213010232]
[18]
Roh, E.J.; Park, Y.H.; Song, C.E.; Oh, S-J.; Choe, Y.S.; Kim, B-T.; Chi, D.Y.; Kim, D. Radiolabeling of paclitaxel with electrophilic 123I. Bioorg. Med. Chem., 2000, 8(1), 65-68.
[http://dx.doi.org/10.1016/S0968-0896(99)00255-2] [PMID: 10968265]
[19]
Vallabhajosula, S.; Nikolopoulou, A. Radioiodinated metaiodobenzylguanidine (MIBG): Radiochemistry, biology, and pharmacology. Semin. Nucl. Med., 2011, 41(5), 324-33.
[http://dx.doi.org/10.1053/j.semnuclmed.2011.05.003]
[20]
Tonnesen, G.L.; Hanson, R.N.; Seitz, D.E. Position-specific radioiodination utilizing an aryltributylstannyl intermediate. Synthesis of 125I-iodotamo-xifen. Appl. Radiat. Isot., 1981, 32(3), 171-173.
[http://dx.doi.org/10.1016/0020-708X(81)90109-5]
[21]
Becke, A.D. A new mixing of Hartree–Fock and local density‐functional theories. J. Chem. Phys., 1993, 98(2), 1372-1377.
[http://dx.doi.org/10.1063/1.464304]
[22]
Frisch, M.; Trucks, G.; Schlegel, H.; Scuseria, G.; Robb, M.; Cheeseman, J.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. Gaussian 09, revision D. 01; Gaussian, Inc.: Wallingford, CT, 2009.
[23]
Tomasi, J.; Mennucci, B.; Cammi, R. Quantum mechanical continuum solvation models. Chem. Rev., 2005, 105(8), 2999-3093.
[http://dx.doi.org/10.1021/cr9904009] [PMID: 16092826]
[24]
Jacquemin, D.; Wathelet, V.; Perpète, E.A.; Adamo, C. Extensive TD-DFT benchmark: Singlet-excited states of organic molecules. J. Chem. Theory Comput., 2009, 5(9), 2420-2435.
[http://dx.doi.org/10.1021/ct900298e] [PMID: 26616623]
[25]
Gauss, J. Effects of electron correlation in the calculation of nuclear magnetic resonance chemical shifts. J. Chem. Phys., 1993, 99, 3629-3643.
[http://dx.doi.org/10.1063/1.466161]
[26]
Parr, R.G.; Yang, W. Density functional approach to the frontier-electron theory of chemical reactivity. J. Am. Chem. Soc., 1984, 106(14), 4049-4050.
[http://dx.doi.org/10.1021/ja00326a036]
[27]
Scrocco, E.; Tomasi, J. Electronic molecular structure, reactivity and intermolecular forces: An euristic interpretation by means of electrostatic molecular potentials. Adv. Quantum Chem., 1978, 11, 115-193. Available at
[http://dx.doi.org/10.1016/S0065-3276(08)60236-1]
[28]
Luque, F.J.; López, J.M.; Orozco, M. Perspective on “Electrostatic interactions of a solute with a continuum. A direct utilization of ab initio molecular potentials for the prevision of solvent effects”. Theor. Chem. Acc., 2000, 103(3-4), 343-345.
[http://dx.doi.org/10.1007/s002149900013]
[29]
Mendoza-Wilson, A.M.; Glossman-Mitnik, D. CHIH-DFT study of the electronic properties and chemical reactivity of quercetin. J. Mol. Struct., 2005, 716(1-3), 67-72.
[http://dx.doi.org/10.1016/j.theochem.2004.10.083]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 4
Year: 2020
Published on: 27 July, 2020
Page: [295 - 303]
Pages: 9
DOI: 10.2174/1570179417666200409145824
Price: $65

Article Metrics

PDF: 17
HTML: 2