Synthesis and In Vitro Evaluation of E- and Z-Geometrical Isomers of PSS232 as Potential Metabotropic Glutamate Receptors Subtype 5 (mGlu₅) Binders

Dedicated to Prof. Scott E. Denmark on the occasion of his 60^th birthday

Abstract

Based on the core structure of [¹¹C]-ABP688, our group developed a novel fluorine-18 labeled PET radiotracer, (E)-[¹⁸F]-PSS232, with significantly improved in vivo properties compared to the earlier fluorine-18 derivative [¹⁸F]-FDEGPECO. The synthetic approach used to obtain PSS232 and the radiolabeling precursor mesylate is disclosed as well as the evaluation of the two geometrical isomers of PSS232. In vitro displacement assays showed higher binding affinity of the E-geometrical isomer (1 nM vs 15 nM, for Z-isomer), which was, for this reason, selected for radiolabeling. One-step radiolabeling conditions (K₂₂₂/¹⁸F^–, DMSO, 95 °C, 10 min) to synthesize (E)-[¹⁸F]-PSS232 from the mesylate via nucleophilic substitution are described. At ambient temperature, (E)-[¹⁸F]-PSS232, with log D _7.4 value of 2.0, was chemically stable over six hours in the presence of sodium ascorbate as a radical scavenger.

Key words

mGlu₅ - PET imaging - PSS223 - PSS232 - ABP688

• References

• 1 Ametamey SM, Honer M, Schubiger PA. Chem. Rev. 2008; 108: 1501
• 2 Burger C, Deschwanden A, Ametamey S, Johayem A, Mancosu B, Wyss M, Hasler G, Buck A. Nucl. Med. Biol. 2010; 37: 845
• 3 Calcinaghi N, Jolivet R, Wyss MT, Ametamey SM, Gasparini F, Buck A, Weber B. J. Cereb. Blood Flow Metab. 2011; 31: e1
• 4 DeLorenzo C, Kumar JS. D, Mann JJ, Parsey RV. J. Cereb. Blood Flow Metab. 2011; 31: 2169
• 5 Deschwanden A, Karolewicz B, Feyissa AM, Treyer V, Ametamey SM, Johayem A, Burger C, Auberson YP, Sovago J, Stockmeier C, Buck A, Hasler G. Am. J. Psychiatry 2011; 168: 727
• 6 Treyer V, Streffer J, Wyss MT, Bettio A, Ametamey SM, Fischer U, Schmidt M, Gasparini F, Hock C, Buck A. J. Nucl. Med. 2007; 48: 1207
• 7 Wyss MT, Ametamey SM, Valerie T, Andrea B, Blagoev M, Kessler LJ, Burger C, Weber B, Schmidt M, Gasparini F, Alfred B. NeuroImage 2007; 35: 1086
• 8 Ametamey SM, Kessler LJ, Honer M, Wyss MT, Buck A, Hintermann S, Auberson YP, Gasparini F, Schubiger PA. J. Nucl. Med. 2006; 47: 698
• 9 Ametamey SM, Treyer V, Streffer J, Wyss MT, Schmidt M, Blagoev M, Hintermann S, Auberson Y, Gasparini F, Fischer UC, Buck A. J. Nucl. Med. 2007; 48: 247
• 10 Hintermann S, Vranesic I, Allgeier H, Bruelisauer A, Hoyer D, Lemaire M, Moenius T, Urwyler S, Whitebread S, Gasparini F, Auberson YP. Bioorg. Med. Chem. 2007; 15: 903
• 11 Brown AK, Kimura Y, Zoghbi SS, Simeon FG, Liow JS, Kreisl WC, Taku A, Fujita M, Pike VW, Innis RB. J. Nucl. Med. 2008; 49: 2042
• 12 Hamill TG, Krause SR. C, Bonnefous C, Govek S, Seiders TG, Cosford NP. D, Roppe J, Kamenecka T, Patel S, Gibson RE, Sanabria S, Riffel K, Eng W, King C, Yang X, Green MD, O’Malley SS, Hargreaves R, Burns HD. Synapse 2005; 56: 205
• 13 Shetty HU, Zoghbi SS, Simeon FG, Liow JS, Brown AK, Kannan P, Innis RB, Pike VW. J. Pharmacol. Exp. Ther. 2008; 327: 727
• 14 Simeon FG, Brown AK, Zoghbi SS, Patterson VM, Innis RB, Pike VW. J. Med. Chem. 2007; 50: 3256
• 15 Wong DF, Waterhouse R, Kuwabara H, Kim J, Brasic JR, Chamroonrat W, Stabins M, Holt DP, Dannals RE, Hamill TG, Mozley PD. J. Nucl. Med. 2013; 54: 388
• 16 Baumann CA, Mu L, Johannsen S, Honer M, Schubiger PA, Ametamey SM. J. Med. Chem. 2010; 53: 4009
• 17 Wanger-Baumann CA, Mu L, Honer M, Belli S, Alf MF, Schubiger PA, Kramer SD, Ametamey SM. NeuroImage 2011; 56: 984
• 18 Sephton SM, Dennler P, Leutwiler D, Mu L, Wanger-Baumann CA, Schibli R, Krämer SD, Ametamey SM. Am. J. Nucl. Med. Mol. Imaging 2012; 2: 14
• 19 Sephton SM, Dennler P, Leutwiler D, Mu L, Schibli R, Krämer SD, Ametamey SM. Chimia 2012; 66: 201
• 20 Testa B, Krämer SD. Chemistry & Biodiversity 2007; 4: 257
• 21 Patent for this work was filed. Application No. 12170914.1-2101, 05.06.2012
• 22 Sephton SM, Mu L, Schweizer WB, Schibli R, Krämer SD, Ametamey SM. J. Med. Chem. 2012; 55: 7154
• 23 Denmark SE, Dappen MS. J. Org. Chem. 1984; 49: 798
• 24 Pretsch E, Clerc JT, Seibl J, Simon W. Tabellen zur Strukturaufklärung organischer Verbindungen mit spektroskopischen Methoden. Springer; Berlin: 1976
• 25 Stothers JB. Carbon-13 NMR Spectroscopy . Academic Press; New York: 1972
• 26 Sakai N, Moriya T, Fujii K, Konakahara T. Synthesis 2008; 3533
• 27 Alagille D, Baldwin RM, Roth BL, Wroblewski JT, Grajkowska E, Tamagnan GD. Bioorg. Med. Chem. 2005; 13: 197
• 28 Quarternary acetylene carbons are overlapped or due to a weak signal one is missing.
• 29 Wilson AA, Jin L, Garcia A, DaSilva JN, Houle S. Appl. Radiat. Isot. 2001; 54: 203