Validation of [ 11 C]MP4A and [ 11 C]MP4P as tracers for quantifying brain ache activity with PET based on in vivo and in vitro human studies

Background

N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) and propionate ([11C]MP4P) have been used for quantification of AChE activity in living humans with PET. Reactivity of [11C]MP4A with AChE is known to be 4–5 times higher than that of [11C]MP4P. On the other hand, distribution of AChE within the brain is not uniform (Table 1), low in cortex (CX), moderate in hippocampus (HP) and thalamus (TH), high in cerebellum (CB)and striatum (ST). In this study, to make a better choice between the two tracers for each brain region of above, precisions and biases of regional k3 values (AChE index) were compared.

Table 1

	CX	HP	TH	CB	ST
AChE	1.0	2.2	3.7	10	51
MP4A_k3	1.0	1.7	2.7	13	13
CV(%)	7.7	12	13	68	80
MP4P_k3	1.0	1.9	2.5	9.1	14
CV(%)	13	14	10	14	26

Methods

Twenty normal subjects for [11C]MP4A and 15 for [11C]MP4P were participated in PET study. Dynamic PET scans were performed over 40 min/14 frames for [11C]MP4A and 60/16 frames for [11C]MP4P with arterial blood sampling for input function measurement. After anatomical normalization of the PET images, dynamic data were obtained from 31 cortical ROIs and 17 non-cortical ROIs, and k3 values (AChE index) were estimated by standard non-linear least squares analysis. Using post-mortem brain tissues, regional AChE activity was measured by Ellman's method.

Results

Except striatum with very high AChE activity, good correlations were obtained between AChE activity and k3 values for [11C]MP4A (R>0. 98) and [11C]MP4P (R>0.99). While [11C]MP4P gave precise k3 in all regions, with 10–26% of coefficient of variation (CV), [11C]MP4A gave acceptable k3 k3 CV only in regions with low to moderate AChE activity (Table 1). However, across 31 cortical ROIs, [11C]MP4A gave significantly lower k3 CV (7.7±0.9%) compared with [11C]MP4P (13.4±2.1%). Sensitivity of [11C]MP4A was about twice that of [11C]MP4P. Interestingly, k3 ratio of [11C]MP4A to [11C]MP4P depended on AChE activity across cortical regions (Figure 1), suggesting that AChE-specificity of [11C]MP4P may be insufficient in cortical regions.

Figure 1

Ratio of MP4A_k3 to MP4P_k3

Conclusion

For whole brain AChE mapping, [11C]MP4P with lower AChE-reactivity is more suitable because of lower k3 CV compared with [11C]MP4A. However, in cortex, [11C]MP4A may be better choice because of lower k3 CV and is expected to have higher sensitivity in detecting cortical AChE reduction in such diseases as Alzheimer's disease and dementia with Lewy bodies.