Login Register Cart 0
Generic placeholder image

Current Radiopharmaceuticals

Editor-in-Chief

ISSN (Print): 1874-4710
ISSN (Online): 1874-4729

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Automated Synthesis of [11C]PiB via [11CH3OTf]-as Methylating Agent for PET Imaging of β-Amyloid

Author(s): Akhilesh K. Singh, Sanjay Gambhir and Manish Dixit*

Volume 17, Issue 3, 2024

Published on: 06 March, 2024

Page: [302 - 311] Pages: 10

DOI: 10.2174/0118744710295705240229114137

Price: $65

Abstract

Aim: Efficient synthesis of precursor from commercially available starting materials and automated radiosynthesis of [11C]PiB using commercially available dedicated [11C]- Chemistry module from the synthesized precursor.

Background: [11C]PiB is a promising radiotracer for PET imaging of β-Amyloid, advancing Alzheimer's disease research. The availability of precursors and protocols for efficient radiolabelling foster the applications of any radiotracer. Efficient synthesis of PiB precursor was performed using anisidine and 4-nitrobenzoyl chloride as starting materials in 5 steps, having addition, substitutions, and cyclization chemical methodologies. This precursor was used for fully automated radiosynthesis of [11C]PiB in a commercially available synthesizer, MPS-100 (SHI, Japan). The synthesized [11C]PiB was purified via solid-phase methodology, and its quality control was performed by the quality and safety criteria required for clinical use.

Methods: The synthesis of desired precursors and standard authentic compounds started with commercially available materials with 70-80% yields. The standard analytical methods were characterized all synthesized compounds. The fully automated [11C]-chemistry synthesizer (MPS-100) used for radiosynthesis of [11C]PiB with [11C]CH3OTf acts as a methylating agent. For radiolabelling, varied amounts of precursor and time of reaction were explored. The resulting crude product underwent purification through solid-phase cartridges. The synthesized radiotracer was analyzed using analytical tools such as radio TLC, HPLC, pH endo-toxicity, and half-life.

Results: The precursor for radiosynthesis of [11C]PiB was achieved in excellent yield using simple and feasible chemistry. A protocol for radiolabelling of precursor to synthesized [11C]PiB was developed using an automated synthesizer. The crude radiotracer was purified by solid-phase cartridge, with a decay-corrected radiochemical yield of 40±5% and radiochemical purity of more than 97% in approx 20 minutes (EOB). The specific activity was calculated and found in a 110-121 mCi/μmol range.

Conclusion: A reliable methodology was developed for preparing precursor followed by fully automated radiolabeling using [11C]MeOTf as a methylating agent to synthesize [11C]PiB. The final HPLC-free purification yielded more than 97% radiochemical purity tracer within one radionuclide half-life. The method was reproducible and efficient for any clinical center.

« Previous
Graphical Abstract

[1]
Selkoe, D.J. The molecular pathology of Alzheimer’s disease. Neuron, 1991, 6(4), 487-498.
[http://dx.doi.org/10.1016/0896-6273(91)90052-2] [PMID: 1673054]
[2]
Villemagne, V.L.; Burnham, S.; Bourgeat, P.; Brown, B.; Ellis, K.A.; Salvado, O.; Szoeke, C.; Macaulay, S.L.; Martins, R.; Maruff, P.; Ames, D.; Rowe, C.C.; Masters, C.L. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: A prospective cohort study. Lancet Neurol., 2013, 12(4), 357-367.
[http://dx.doi.org/10.1016/S1474-4422(13)70044-9] [PMID: 23477989]
[3]
Carrillo, M.C.; Brashear, H.R.; Logovinsky, V.; Ryan, J.M.; Feldman, H.H.; Siemers, E.R.; Abushakra, S.; Hartley, D.M.; Petersen, R.C.; Khachaturian, A.S.; Sperling, R.A. Can we prevent alzheimer’s disease? secondary “prevention” trials in alzheimer’s disease. Alzheimers Dement., 2013, 9(2), 123-131.e1.
[http://dx.doi.org/10.1016/j.jalz.2012.12.004] [PMID: 23411394]
[4]
Bateman, R.J.; Xiong, C.; Benzinger, T.L.S.; Fagan, A.M.; Goate, A.; Fox, N.C.; Marcus, D.S.; Cairns, N.J.; Xie, X.; Blazey, T.M.; Holtzman, D.M.; Santacruz, A.; Buckles, V.; Oliver, A.; Moulder, K.; Aisen, P.S.; Ghetti, B.; Klunk, W.E.; McDade, E.; Martins, R.N.; Masters, C.L.; Mayeux, R.; Ringman, J.M.; Rossor, M.N.; Schofield, P.R.; Sperling, R.A.; Salloway, S.; Morris, J.C. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med., 2012, 367(9), 795-804.
[http://dx.doi.org/10.1056/NEJMoa1202753] [PMID: 22784036]
[5]
Braak, H.; Braak, E. Neuropathological stageing of alzheimer-related changes. Acta Neuropathol., 1991, 82(4), 239-259.
[http://dx.doi.org/10.1007/BF00308809] [PMID: 1759558]
[6]
Mirra, S.S.; Heyman, A.; McKeel, D.; Sumi, S.M.; Crain, B.J.; Brownlee, L.M.; Vogel, F.S.; Hughes, J.P.; Belle, G.; Berg, L. The consortium to establish a registry for alzheimer’s disease (CERAD). Neurology, 1991, 41(4), 479-486.
[http://dx.doi.org/10.1212/WNL.41.4.479] [PMID: 2011243]
[7]
Klunk, W.E.; Abraham, D.J. Filamentous proteins in alzheimer’s disease: New insights through molecular biology. Psychiatr. Dev., 1988, 6(2), 121-152.
[PMID: 2907135]
[8]
Näslund, J.; Haroutunian, V.; Mohs, R.; Davis, K.L.; Davies, P.; Greengard, P.; Buxbaum, J.D. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA, 2000, 283(12), 1571-1577.
[http://dx.doi.org/10.1001/jama.283.12.1571] [PMID: 10735393]
[9]
Lee, J.C.; Kim, S.J.; Hong, S.; Kim, Y.S. Diagnosis of alzheimer’s disease utilizing amyloid and tau as fluid biomarkers. Exp. Mol. Med., 2019, 51(5), 1-10.
[http://dx.doi.org/10.1038/s12276-019-0250-2]
[10]
Huff, F.J.; Becker, J.T.; Belle, S.H.; Nebes, R.D.; Holland, A.L.; Boller, F. Cognitive deficits and clinical diagnosis of alzheimer’s disease. Neurology, 1987, 37(7), 1119-1124.
[http://dx.doi.org/10.1212/WNL.37.7.1119] [PMID: 3601078]
[11]
Testa, G.; Staurenghi, E.; Zerbinati, C.; Gargiulo, S.; Iuliano, L.; Giaccone, G.; Fantò, F.; Poli, G.; Leonarduzzi, G.; Gamba, P. Changes in brain oxysterols at different stages of Alzheimer’s disease: Their involvement in neuroinflammation. Redox Biol., 2016, 10, 24-33.
[http://dx.doi.org/10.1016/j.redox.2016.09.001] [PMID: 27687218]
[12]
Zarrouk, A.; Hammouda, S.; Ghzaiel, I.; Hammami, S.; Khamlaoui, W.; Ahmed, S.H.; Lizard, G.; Hammami, M. Association between oxidative stress and altered cholesterol metabolism in alzheimer’s disease patients. Curr. Alzheimer Res., 2021, 17(9), 823-834.
[http://dx.doi.org/10.2174/1567205017666201203123046] [PMID: 33272182]
[13]
Holtzman, D.M.; Bales, K.R.; Paul, S.M.; DeMattos, R.B. Aβ immunization and anti-Aβ antibodies: Potential therapies for the prevention and treatment of alzheimer’s disease. Adv. Drug Deliv. Rev., 2002, 54(12), 1603-1613.
[http://dx.doi.org/10.1016/S0169-409X(02)00158-8] [PMID: 12453677]
[14]
Olson, R.E.; Copeland, R.A.; Seiffert, D. Progress towards testing the amyloid hypothesis: Inhibitors of APP processing. Curr. Opin. Drug Discov. Devel., 2001, 4(4), 390-401.
[PMID: 11727304]
[15]
Matsuoka, Y.; Saito, M.; LaFrancois, J.; Saito, M.; Gaynor, K.; Olm, V.; Wang, L.; Casey, E.; Lu, Y.; Shiratori, C.; Lemere, C.; Duff, K. Novel therapeutic approach for the treatment of alzheimer’s disease by peripheral administration of agents with an affinity to β-amyloid. J. Neurosci., 2003, 23(1), 29-33.
[http://dx.doi.org/10.1523/JNEUROSCI.23-01-00029.2003] [PMID: 12514198]
[16]
Del Sole, A.; Malaspina, S.; Magenta Biasina, A. Magnetic resonance imaging and positron emission tomography in the diagnosis of neurodegenerative dementias. Funct. Neurol., 2016, 31(4), 205-215.
[PMID: 28072381]
[17]
Rosenberg, P.B.; Wong, D.F.; Edell, S.L.; Ross, J.S.; Joshi, A.D.; Brašić, J.R.; Zhou, Y.; Raymont, V.; Kumar, A.; Ravert, H.T.; Dannals, R.F.; Pontecorvo, M.J.; Skovronsky, D.M.; Lyketsos, C.G. Cognition and amyloid load in Alzheimer disease imaged with florbetapir F 18(AV-45) positron emission tomography. Am. J. Geriatr. Psychiatry, 2013, 21(3), 272-278.
[http://dx.doi.org/10.1016/j.jagp.2012.11.016] [PMID: 23395194]
[18]
Villemagne, V.L.; Ong, K.; Mulligan, R.S.; Holl, G.; Pejoska, S.; Jones, G.; O’Keefe, G.; Ackerman, U.; Tochon-Danguy, H.; Chan, J.G.; Reininger, C.B.; Fels, L.; Putz, B.; Rohde, B.; Masters, C.L.; Rowe, C.C. Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias. J. Nucl. Med., 2011, 52(8), 1210-1217.
[http://dx.doi.org/10.2967/jnumed.111.089730] [PMID: 21764791]
[19]
Jennings, D.; Seibyl, J.; Sabbagh, M.; Lai, F.; Hopkins, W.; Bullich, S.; Gimenez, M.; Reininger, C.; Putz, B.; Stephens, A.; Catafau, A.M.; Marek, K. Age dependence of brain β-amyloid deposition in Down syndrome. Neurology, 2015, 84(5), 500-507.
[http://dx.doi.org/10.1212/WNL.0000000000001212] [PMID: 25568295]
[20]
Vandenberghe, R.; Van Laere, K.; Ivanoiu, A.; Salmon, E.; Bastin, C.; Triau, E.; Hasselbalch, S.; Law, I.; Andersen, A.; Korner, A.; Minthon, L.; Garraux, G.; Nelissen, N.; Bormans, G.; Buckley, C.; Owenius, R.; Thurfjell, L.; Farrar, G.; Brooks, D.J. 18 Fflutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial. Ann. Neurol., 2010, 68(3), 319-329.
[http://dx.doi.org/10.1002/ana.22068] [PMID: 20687209]
[21]
Bi, X.; Xu, B.; Liu, J.; Wang, G.; An, J.; Zhang, X.; Wang, R.; Dong, W.; Guan, Z. Diagnostic value of 11C-PIB PET/MR in cardiac amyloidosis. Front. Cardiovasc. Med., 2022, 9, 830572.
[http://dx.doi.org/10.3389/fcvm.2022.830572] [PMID: 35369284]
[22]
Ezawa, N.; Katoh, N.; Oguchi, K.; Yoshinaga, T.; Yazaki, M.; Sekijima, Y. Visualization of multiple organ amyloid involvement in systemic amyloidosis using 11C-PiB PET imaging. Eur. J. Nucl. Med. Mol. Imaging, 2018, 45(3), 452-461.
[http://dx.doi.org/10.1007/s00259-017-3814-1] [PMID: 28891012]
[23]
Mathis, C.A.; Bacskai, B.J.; Kajdasz, S.T.; McLellan, M.E.; Frosch, M.P.; Hyman, B.T.; Holt, D.P.; Wang, Y.; Huang, G.F.; Debnath, M.L.; Klunk, W.E. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg. Med. Chem. Lett., 2002, 12(3), 295-298.
[http://dx.doi.org/10.1016/S0960-894X(01)00734-X] [PMID: 11814781]
[24]
Mathis, C.A.; Wang, Y.; Holt, D.P.; Huang, G.F.; Debnath, M.L.; Klunk, W.E. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J. Med. Chem., 2003, 46(13), 2740-2754.
[http://dx.doi.org/10.1021/jm030026b] [PMID: 12801237]
[25]
Parker, T.D. Investigating the relationship between β-amyloid and grey matter macrostructure and microstructure in ageing and dementia; , 2019. Available from: https://discovery.ucl.ac.uk/id/eprint/10067324
[26]
Hyde, D.; Dekleine, R.; MacLaurin, S.; Miller, E.; Brooks, D.; Krucker, T.; Ntziachristos, V. Hybrid FMT–CT imaging of amyloid-β plaques in a murine alzheimer’s disease model. Neuroimage, 2009, 44(4), 1304-1311.
[http://dx.doi.org/10.1016/j.neuroimage.2008.10.038] [PMID: 19041402]
[27]
a) Rabinovici, GD.; Furst, AJ.; O’neil, JP.; Racine, CA.; Mormino, EC.; Baker, SL.; Chetty, S.; Patel, P.; Pagliaro, TA.; Klunk, WE.; Mathis, CA. 11C-PIB PET imaging in alzheimerdisease and frontotemporal lobar degeneration. Neurology, 2007, 68(15), 1205-1212.;
b) Bose, D.S.; Mohd, I. A convenient access to substituted benzothiazole scaffolds via intramolecular cyclization of thioformanilides. Tetrahedron Lett., 2007, 48(4), 669-672.;
c) Clemente, G.; Alves, V.; Abrunhosa, A. J.; Uzun, A.; Bilgic, S.; Tontus, H.O. Synthesis optimization of pittsburgh compound B by the captive solvent method. IEEE 2nd Portuguese Meeting in Bioengineering (ENBENG), Coimbra, Portugal, 23-25 February 2012, pp. 1-4.
[PMID: 18769311];
d) Verdurand, M.; Mathieu, B.; Guillaume, B.; Vincent, T.; Frederic, B.; Didier, L.B.; Luc, Z. Automated radiosynthesis of the Pittsburg compound-B using a commercial synthesizer. Nucl. Med. Commun., 2008, 29(10), 920-926.
[28]
Solbach, C.; Uebele, M.; Reischl, G.; Machulla, H.J. Efficient radiosynthesis of carbon-11 labelled uncharged Thioflavin T derivatives using [11C]methyl triflate for -amyloid imaging in alzheimer’s disease with PET. Appl. Radiat. Isot., 2005, 62(4), 591-595.
[http://dx.doi.org/10.1016/j.apradiso.2004.09.003] [PMID: 15701414]
[29]
Philippe, C.; Haeusler, D.; Mitterhauser, M.; Ungersboeck, J.; Viernstein, H.; Dudczak, R.; Wadsak, W. Optimization of the radiosynthesis of the alzheimer tracer 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB). Appl. Radiat. Isot., 2011, 69(9), 1212-1217.
[http://dx.doi.org/10.1016/j.apradiso.2011.04.010] [PMID: 21550258]
[30]
Andersson, J.; Truong, P.; Halldin, C. In-target produced [11C]methane: Increased specific radioactivity. Appl. Radiat. Isot., 2009, 67(1), 106-110.
[http://dx.doi.org/10.1016/j.apradiso.2008.09.010] [PMID: 19013077]
[31]
Jewett, D.M. A simple synthesis of [11C]methyl triflate. Int. J. Rad. Appl. Instrum. [A], 1992, 43(11), 1383-1385.
[http://dx.doi.org/10.1016/0883-2889(92)90012-4] [PMID: 1333459]
[32]
Holschbach, M.; Schüller, M. An on-line method for the preparation of n.c.a. [11CH3]trifluoromethanesulfonic acid methyl ester. Appl. Radiat. Isot., 1993, 44(5), 897-898.
[http://dx.doi.org/10.1016/0969-8043(93)90035-9]
[33]
Taddei, C.; Pike, V.W. [11C]Carbon monoxide: Advances in production and application to PET radiotracer development over the past 15 years. EJNMMI Radiopharm. Chem., 2019, 4(1), 25.
[http://dx.doi.org/10.1186/s41181-019-0073-4] [PMID: 31659516]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy