Cerebral and myocardial kinetics of [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate: A comparative crossover study in healthy rats

Background: Ketone metabolism has been studied using positron emission tomography (PET) with the radiotracers [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate. However, whether these two radiotracers actually yield equivalent estimates of cerebral and myocardial ketone metabolism has not yet been investigated. This study aimed to investigate and compare the kinetics of both tracers in the brain and heart of healthy rats under varying levels of circulating ketones at baseline and after a single-dose exogenous ketone ester (KE) supplement.

Methods: Six healthy Sprague-Dawley rats each underwent two scans with each tracer: one following oral KE administration and one with a placebo. Cerebral kinetic parameters (K_i, V_T, and cerebral metabolic rate (CMR)) were obtained using the Patlak method, whereas myocardial kinetic parameters (K₁, k₂, and V_T) were derived using a 1-tissue compartment model. Parameters were compared through mixed-effects, correlation, and Bland-Altman analyses.

Results: Global CMR increased 3-4-fold in the KE group versus placebo, with strong positive correlations between CMR and plasma ketone levels for both tracers. Correlations between [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate were moderate and non-significant for relative cerebral uptake expressed as K_i (ρ = 0.40) and for V_T (ρ = 0.38) but strongly positive for absolute uptake, CMR (r = 0.84), with a non-significant mean bias of -0.03. In contrast, myocardial kinetics showed only non-significant weak to moderate correlations between the radiotracers (K₁ (r = 0.04), k₂ (r = -0.27), and V_T (ρ = 0.43)), with no systematic biases.

Conclusion: [¹¹C]acetoacetate and [¹¹C]β-hydroxybutyrate can be used interchangeably for measuring global CMR in healthy rats but differ in certain cerebral and myocardial kinetics. Whether these findings are generalizable to pathological conditions warrants further studies to explore the kinetics of these tracers in disease models.