Evaluation of [11C]KB631 as a PET tracer for in vivo visualisation of HDAC6 in B16.F10 melanoma

Abstract

Evaluation of [ 11 C]KB631 as a PET tracer for in vivo visualisation of HDAC6 in B16.F10 melanoma

Radiosynthesis and preliminary evaluation of an18F‐labeled tubastatin A analog for PET imaging of histone deacetylase 6

“…Regarding the development of HDAC6-selective radioligands, Lu et al reported on 11 C-carbonylation methods for labeling tubastatin A, an HDAC6-selective inhibitor (1 in Figure 1), 36 that employed [ 11 C]carbon monoxide. 37 Radiosynthesis of the tubastatin A analog [ 11 C]KB631 ([ 11 C]2 in Figure 1) with [ 11 C]methyl iodide was also reported by Lu et al, 38 and its preclinical evaluation for visualization of B16F10 melanoma has recently been reported by Vermeulen et al 39 Additionally, [ 18 F] Bavarostat was developed by Strebl et al 40 as an adamantane-conjugated HDAC6-selective radioligand. Although [ 18 F]Bavarostat needs a unique rutheniummediated 18 F-deoxyfluorination 41 for its radiosynthesis, its BBB permeability and specific binding in the brain was confirmed by in vivo blocking studies in nonhuman primates.…”

“…Excellent stability of [ 11 C]2 was demonstrated in plasma radio-metabolite analysis in mice 39 ; therefore, the comparison of pharmacokinetics between the radioligands could reveal the influence of structural modifications, such as the introduction of an [ 18 F]fluoroethyl moiety, of [ 18 F]3 on its pharmacokinetics. 38,39 Similarly, brain uptake of [ 18 F]3 was low and stable at around 0.5% ID/g over a 60-minute period. Similarly, in some organs, the radioactivity uptake of [ 18 F]3-injected mice was significantly higher than that observed with [ 11 C]2-injected mice, including the heart, lung, liver, and muscle, at the early time points.…”

“…47 The development and function of the testis of HDAC6 knockout mice are normal, 48 whereas inhibition of HDAC6 restricts sperm motility in rats through increased levels of acetyl α-tubulin, which is a component of microtubules in the flagella. 39 Therefore, use of [ 18 F]3 for PET imaging of these cancers is justified. As with the brain, the testis has a blood-testis barrier to protect spermatocytogenesis from toxicants in the systemic circulation and autoimmune responses 50 ; therefore, the barrier may inhibit testis uptake of the radioligands.…”

“…The biodistribution of [ 11 C]2 and [ 18 F]3 from 1 to 60 minutes post injection was evaluated in normal mice ( Table 2). Excellent stability of [ 11 C]2 was demonstrated in plasma radio-metabolite analysis in mice 39 ; therefore, the comparison of pharmacokinetics between the radioligands could reveal the influence of structural modifications, such as the introduction of an [ 18 F]fluoroethyl moiety, of [ 18 F]3 on its pharmacokinetics. The initial blood radioactivity of [ 18 F]3 was higher than that of [ 11 C]2 (4.3% ID/g versus 2.3% ID/g at 2 min post injection), although both radioactivity levels gradually decreased over time and reached the same degree at 60 minutes post injection.…”

“…that employed [ 11 C]carbon monoxide 37. Radiosynthesis of the tubastatin A analog [ 11 C]KB631 ([ 11 C]2 inFigure 1) with [ 11 C]methyl iodide was also reported by Lu et al,38 and its preclinical evaluation for visualization of B16F10 melanoma has recently been reported by Vermeulen et al39 Additionally, [ 18 F] Bavarostat was developed by Strebl et al 40 as an adamantane-conjugated HDAC6-selective radioligand. Although [ 18 F]Bavarostat needs a unique rutheniummediated 18 F-deoxyfluorination…”