[ 11 C]Befloxatone Distribution is well Correlated to Monoamine Oxidase a Protein Levels in the Human Brain

In a recent work, Tong et al reported the in vitro region-wise distribution of protein levels of monoamine oxidase A (MAO-A) in the human brain. ¹ These results have important implications for brain imaging studies. Using data from published positron emission tomography (PET) studies, they found good correlations between in vitro MAO-A levels and PET measures of MAO-A density/activity using [¹¹C]harmine (r=0.86, P = 0.003) and [¹¹C]clorgyline (r=0.82, P = 0.007), but not with [¹¹C]befloxatone (r=0.61, P = 0.15), essentially because of the low [¹¹C]befloxatone binding potential reported in the thalamus. ² Thus, the authors suggested caution in interpretation of the data obtained with this radioligand. Two hypotheses can be put forward to explain this poor correlation: (1) the in vivo kinetics of [¹¹C]befloxatone poorly reflect the actual MAO-A distribution, and therefore [¹¹C]befloxatone should be abandoned; (2) the selected quantitative parameter, (k₃/k₄), is not the optimal one, and thus a different outcome parameter should be chosen.

The full kinetic modeling of [¹¹C]befloxatone has been recently published. ³ This study showed that a two-tissue compartment model can reliably quantify total distribution volume (V_T) values. In agreement with in vitro data, the lowest [¹¹C]befloxatone V_T values were found in the cerebellum (6.7 ± 0.9 ml/cm³), while the highest were in the thalamus (19.3 ± 1.4 ml/cm³). ³ Importantly, [¹¹C]befloxatone V_T values are well correlated with the in vitro MAO-A protein levels published by Tong et al., ¹ to a degree similar to that found for the other MAO-A radioligands (r = 0.78, P = 0.008) (Figure 1). Notably, the thalamus/cerebellum V_T ratio is slightly higher for [¹¹C]befloxatone (2.9), than for [¹¹C]harmine V_S (2.1) and [¹¹C]clorgyline Λλk₃ (2.4), thus indicating a slightly better, although still imperfect, quantitative proportionality with in vitro data (3.9). ¹ Furthermore, [¹¹C]befloxatone compartmental V_T values are well correlated not only with protein levels, but also with mRNA expression of MAO-A, ⁴ which suggests that MAO-A undergo little in vivo post-transcriptional modifications.

One possible reason why (k₃/k₄) showed a poor correlation with protein levels might be due to the very slow wash-out from the brain of [¹¹C]befloxatone, ³ which may introduce errors in the estimation of microparameters, especially k₄. In addition, a K₁/k₂ constrained model presupposes a constant non-displaceable compartment across the brain. If this condition is not verified, a regional quantification error may ensue.

OPEN IN VIEWER

Figure 1.

Correlation between [¹¹C]befloxatone V_T values and in vitro MAO-A protein levels. Please compare this figure to Figure 6 in the paper by Tong and colleagues ¹ .

Finally, in our kinetic modeling paper, we also showed that spectral analysis provided the most reliable quantification of [¹¹C]befloxatone at the voxel level. ³ However, the correlation between protein levels and voxel-wise spectral analysis V_T values is weaker than with compartmental modeling (r = 0.67, P = 0.033). Therefore, compartmental modeling at the regional level should be the method of choice to quantify [¹¹C]befloxatone binding.

In summary, [¹¹C]befloxatone can reliably quantify MAO-A concentrations in human PET studies, and its preferred outcome measure should be V_T estimated by compartmental modeling.