Abstract
242006
Introduction: Organosilanes are important cross-coupling nucleophiles in several processes, such as metal-mediated radiolabeling with 11C-labeled derivatives for positron emission tomography (PET). Our groups previously developed and optimized a novel radiocyanation of aryl heptamethyltrisiloxane precursors under a CuII/CuIII reaction manifold.[1] These precursors are a promising alternative to commonly employed aryl borons and stannanes, which can have limitations such as poor bench-top stability (e.g., 2-azaaryl boronates) or high cumulative neurotoxicity (e.g., trialkyl stannanes), respectively. Herein, we describe the successful application of this radiolabeling methodology to an electronically diverse profile of (hetero)aromatic heptamethyltrisiloxanes in high conversions.
Methods: A GE PETtrace cyclotron (60 μA) was used to produce [11C]CO2 by the 14N(p,α)11C nuclear reaction. In a GE Process Cabinet, [11C]CO2 was briefly trapped on molecular sieves at room temperature. The released [11C]CO2 was mixed with H2 at 350 °C and passed through a 400 °C Ni oven, producing [11C]CH4. [11C]CH4 was purified through Ascarite® and Sicapent® columns. The [11C]CH4 and anhydrous NH3 were passed through a 950 °C Pt oven, forming [11C]HCN. The [11C]HCN was then treated with a potassium salt to afford [11C]KCN, which was incorporated into various aryl silanes under the optimized reaction conditions (vide supra).
Results: Various silanes were conveniently prepared from aryl iodides with Pd/Pt catalysis, aryl C-H precursors with Ir/Rh catalysis, or dialkoxymethyl(aryl)silanes via transetherification. Electron-rich and -deficient (hetero)aromatic benzonitriles exhibited excellent conversions, with the former substrate class exhibiting the highest efficiency. Analogous organoboron and organotin precursors had comparable or inferior conversions to heptamethyltrisiloxanes, demonstrating the high radiosynthetic utility of silane precursors. To demonstrate the clinical feasibility of this method, we developed a fully automated two-step protocol that delivers [11C]LY2795050 (vide supra), a PET agent used to image the κ-opioid receptor.[2] Using a stable heptamethyltrisiloxane precursor for this transformation addresses a key challenge with other precursors, such as the corresponding boronate, which exhibits poor bench-top stability. Under automated conditions, the reaction components were sequentially added to a GE TracerLab FX reactor containing [11C]KCN (ca. 3 Ci at the end of bombardment) and N(CH3)4F·4H2O in dimethylacetamide (DMA) and heated at 100 °C for 5 min. The in situ-generated benzonitrile was hydrolyzed with NaOH/H2O2 before semi-preparative HPLC purification and reformulation to afford the corresponding benzamide (>100 mCi).
Conclusions: We present a broad labeling scope in the copper-mediated radiocyanation of (hetero)aromatic heptamethylsiloxanes, which offer improved stability/toxicity profiles to analogous labeling precursors. An efficient automated protocol amenable to the radiosynthesis of PET imaging agents, including a κ-opioid receptor imaging agent, has been developed. Therefore, this methodology can be conveniently leveraged by radiochemists for the preparation of aromatic carbon-11 labeled PET imaging scaffolds, especially in instances where the routine production of (pre)clinical radiomedicines is challenged by precursor/reagent stability and/or toxicity.
Acknowledgments: This work was supported by NIH NIBIB R01EB021155 and K99EB031564.
References:
[1] J. Wright, J. Priest, R. Ma, E. Webb, A. Brooks, M. Sanford, P. J. H. Scott, J Nucl Med 2023, 64(1), 896.
[2] T. Kaur, X. Shao, M. Horikawa, L. S. Sharninghausen, S. Preshlock, A. F. Brooks, B. D. Henderson, R. A. Koeppe, A. F. DaSilva, M. S. Sanford, P. J. H. Scott, Org. Process Res. Dev. 2023, 27, 373
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.