Sigma-2 selective fluorinated ligands: Synthetic method and optimization of decarbonylation for radiolabeling.

Sigma receptors are membrane-bound proteins having high affinities for a variety psychotropic
drugs with opiate-type structures. The sigma receptor subtypes, sigma-1 and sigma-2, have different molecular weights and pharmacological roles.1 Many cancer cell lines (breast, melanoma, prostate cancer) express high levels of sigma receptors,2,3 and proliferative tumor cells express much higher levels of sigma-2 receptors than quiescent cells.4,5 Thus, the sigma-2 receptor has been proposed as a suitable target for imaging proliferative tumor cells.

While many ligands are selective for the sigma-1 receptor or are nonselective, very few ligands
are selective for the sigma-2 receptor. A radiopharmaceutical based on an azabicyclo[3.3.1]nonane framework was developed by Mach,6 who demonstrated that the rhenium surrogate showed exceptional sigma-2 selectivity; later this agent was labeled with technetium-99m by Kung for tissue distribution studies.7 In considering potential fluorine-18
labeled sigma-2 receptor ligands, our attention focused on members of an indole piperidine series, especially 1 (LU 28-179), which is reported to have a remarkably high sigma-2 binding affinity and selectivity.8,9 Figure 1. The structure of indole piperidine ligands and their inhibition constants toward sigma receptors.

Target compounds 1 and 2 were prepared in several steps by a route based on a previously
described method,7 with modifications making it more efficient for the synthesis of the precursor molecule (3); compounds 1 and 2 showed high binding affinity and good selectivity (6 fold) for the sigma-2 receptor (Figure 1). The preparation of [¹⁸F]-labeled indole piperidine [¹⁸F]1 was achieved in two steps from a o-nitroaldehyde precursor (3). Aromatic [¹⁸F]fluorination was not reproducible when 3 was treated with F-18 fluoride in the presence of Bu4NOH under microwave heating conditions. However, by using F-18, K₂CO₃ and kryptofix[2.2.2] under microwave heating, we obtained radiochemical yields of 5-50%. The final decarbonylation step with Wilkinson’s catalyst was studied in various solvents. Decarbonylation using dioxane as solvent produced [¹⁸F]1, but with toluene, extensive decomposition resulted. Herein, we present the synthesis of precursor 3, optimization of [¹⁸F]fluorination, and decarbonylation to produce [¹⁸F]Lu 28-179 (Scheme 1). Future work to prepare [¹⁸F]1 will be done using an alternate synthetic route.10
Supported by DOE grants 86ER60401 (to JAK) and 84ER60218 (to MJW).
Ref)
1. Vilner, B. J. et al. Cancer Res. 55: 408-413 (1995)
2. John, C. S. et al. Cancer Res. 59: 4578-4583 (1999)
3. Quirion, R. et al. Trends Phrmacol. Sci. 13: 85-6 (1992)
4. Mach, R. H. et al. Cancer Res. 57: 156-161 (1997)
5. Wheeler, K. T. et al. Br. J. Cancer 82: 1223-1232 (2000)
6. Mach et al., J. Labelled Cmpds Radiopharm 2001; 44: 899-908
7. Choi, S.-R. Nucle. Med. Biol. 28: 657-666 (2001)
8. Perregaard, J. J. Med. Chem. 38: 1998-2008 (1995)
9. Moltzen, E. K. J. Med. Chem. 38: 2009-2017 (1995)
10. Wüst, F. et al. J. Label. Compd. Radiopharm. 48: 31-43 (2005)