Exploration of the labeling of [¹¹C]tubastatin A at the hydroxamic acid site with [¹¹C]carbon monoxide

We aimed to label tubastatin A (1) with carbon-11 (t_1/2 = 20.4 min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 in vivo with positron emission tomography. Initial attempts at a one-pot Pd-mediated insertion of [¹¹C]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (<5%) of [¹¹C]1. Labeling was achieved in useful radiochemical yields (16.1 ± 5.6%, n = 4) through a two-step process based on Pd-mediated insertion of [¹¹C]carbon monoxide between the aryl iodide (2) and p-nitrophenol to give the [¹¹C]p-nitrophenyl ester ([¹¹C]5), followed by ultrasound-assisted hydroxyaminolysis of the activated ester with excess hydroxylamine in a DMSO/THF mixture in the presence of a strong phosphazene base P₁-t-Bu. However, success in labeling the hydroxamic acid group of [¹¹C]tubastatin A was not transferable to the labeling of three other model hydroxamic acids.