In PET imaging, all second-generation radioligands, including the three highlighted in this review, are sensitive to varying degrees to the rs6971 SNP.
11C-PBR28, DPA-713, and ER176 showed HABs/MABs ratios for
BP
ND of 2.4, 2.1, and 1.2, respectively, whereas (
R)-PK11195 showed similar
BP
ND for HABs and MABs (Table
1). However, the genotype sensitivity of
11C-(
R)-PK11195 is controversial, and the quantitative measurement of specific binding in human brain provides a potential explanation. Specifically, all reports to date show no statistically significant difference in
V
T of
11C-(
R)-PK11195 among three genotypes (HABs vs MABs vs LABs), but the sample sizes have been small. As we now know, the amount of specific binding in brain of
11C-(
R)-PK11195 is quite small,
BP
ND = 0.8 [
10], leading to greater variability and the need for much larger sample sizes to detect statistically significant differences. This theory is supported by the finding that
11C-(
R)-PK11195 is sensitive to genotype in peripheral organs such as lung and heart, which have much greater specific binding than brain [
5]. Although direct measurements from brain are not definitive, we suspect that
11C-(
R)-PK11195 is actually sensitive to genotype in brain under in vivo conditions, similar to the pattern observed in peripheral organs, but the low amount of specific binding of this radioligand requires much larger samples sizes to confirm a statistically significant effect. In vitro binding assay using
3H-PK11195 showed little sensitivity to the genotype [
2]. It should be noted that the sensitivity to the genotype can differ between in vivo (PET) and in vitro binding as we reported for ER176 [
3,
11]. A possible cause of the difference is disruption of protein-protein interactions by tissue homogenization for in vitro binding assays.
Table 1
Distribution volume and the time stability of four 11C–radioligands to image translocator protein (TSPO)
Ligand | HABs | HABs | MABs | LABs | LABs | HABs after blockade |
11C-(R)-PK11195 | 0.7 | 0.8 | 0.9 | 0.5 | 26% | 27% |
11C–PBR28 | 4.3 | 1.2 | 0.5b
| Not reliably measured | Not reliably measured [6] | 25% |
11C–DPA-713 | 3.6 | 7.3 | 3.4b
| 1.8b
| 25% | 13% |
11C–ER176 | 3.3 | 4.2 | 3.4b
| 1.4b
| ~0% | 6% |