Supplemental Data

Supplemental Figure 1. Individual model fits to parent fraction, plasma/blood and input function data 18 Supplemental Figure 2. Linear regression plots comparing (A)MA1 vs 2TC derived F-BCPP-EF VT,

11 11 (B)MA1 vs 2TC derived C-SA-4503 VT, (C)MA1 vs 1TC derived C-UCB-J VT.

THE JOURNAL OF NUCLEAR MEDICINE • Vol. 61• No. 1 • xxx 2019 Mansur et al. 18 Supplemental Figure 3. Regional time stability plots for F-BCPP-EF VT. CS: Centrum semiovale, BST:

Brainstem, SN: substantia nigra, THA: thalamus, VST: ventral striatum, CAU: caudate, PUT: putamen, HIP: hippocampus, INS: insular cortex, Tl; temporal lobe, PL: parietal lobe, FTCX: frontal cortex, CER: cerebellum

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11 Supplemental Figure 4. Regional time stability plots for C-SA-4503 VT. CS: Centrum semiovale, BST:

THE JOURNAL OF NUCLEAR MEDICINE • Vol. 61• No. 1 • xxx 2019 Mansur et al. 11 Supplemental Figure 5. Regional time stability plots for C-UCB-J VT. CS: Centrum semiovale, BST:

Brainstem, SN: substantia nigra, THA: thalamus, VST: ventral striatum, CAU: caudate, PUT: putamen,

HIP: hippocampus, INS: insular cortex, Tl; temporal lobe, PL: parietal lobe, FTCX: frontal cortex, CER: cerebellum

THE JOURNAL OF NUCLEAR MEDICINE • Vol. 61• No. 1 • xxx 2019 Mansur et al. 18 Supplemental Figure 6. Linear regression plots of age vs. (A)DVR and (B)VT/fp estimates for F-BCPP-EF for 11C-SA-4503 and for 11C-UCB-J.

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Supplemental Figure 7. Linear regression plots for age vs fp

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Supplemental Table 1. Demographic information and individual scan parameters

Scan parameters Demographic Data 18F-BCPP-EF 11C-SA-4503 11C-UCB-J

Inj. Inj. Inj. Inj. Inj. Inj. Age MMSE Sex Act Mass fp Act Mass fp Act Mass fp (y) score (MBq) (g) (MBq) (g) (MBq) (g)

M 56 29 87 0.03 0.07 257 3.10 0.07 250 3.43 0.27

M 75 30 94 0.04 0.06 281 2.82 0.05 234 1.85 0.21

F 67 29 89 0.04 0.09 267 2.29 0.05 176 1.61 0.19

F 65 30 97 0.13 0.09 277 5.23 0.07 113 1.45 0.21

M 46 29 91 0.07 0.07 244 2.41 0.06 191 2.05 0.25

M 69 28 87 0.06 0.07 221 2.86 0.06 261 6.26 0.25

M 68 28 91 0.05 0.07 229 1.84 0.06 234 1.82 0.21

F 50 30 91 0.05 0.06 255 2.01 0.05 230 2.12 0.21

F 69 30 96 0.11 0.10 236 1.47 0.06 278 2.23 0.24

F 33 30 85 0.04 0.07 219 5.43 0.05 249 2.60 0.26

M 73 29 82 0.09 0.08 252 3.28 0.10 245 3.53 0.23

M 64 28 88 0.12 0.08 277 3.10 0.10 152 2.54 0.25

Mean 61 29 90 0.07 0.08 251 2.99 0.07 218 2.62 0.23

SD 13 1 4 0.03 0.01 22 1.23 0.02 49 1.32 0.03

COV 20% 3% 5% 50% 16% 9% 41% 27% 23% 50% 11%

fp=plasma free fraction; MMSE=Mini-Mental state exam

*Radiochemical purities were over 98% for all three tracers.

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Supplemental Table 2. Mass effects on PET outcome measures

18F-BCPP-EF 11C-SA-4503 11C-UCB-J ROI r p r p r p

Centrum semiovale 0.50 0.10 -0.26 0.42 -0.07 0.83

Brainstem 0.42 0.17 0.33 0.29 0.10 0.75

Substantia nigra 0.69 0.01 0.32 0.32 0.19 0.55

Thalamus 0.36 0.25 0.21 0.51 -0.10 0.76

Ventral striatum 0.45 0.14 0.32 0.31 -0.09 0.78

Caudate 0.08 0.80 0.16 0.62 -0.25 0.44

Putamen 0.56 0.06 0.22 0.49 -0.11 0.74

Hippocampus 0.49 0.10 0.14 0.67 0.05 0.88

Insular cortex 0.52 0.09 0.05 0.87 0.01 0.98

Temporal lobe 0.51 0.09 0.14 0.66 0.01 0.97

Parietal lobe 0.52 0.08 0.19 0.56 0.07 0.83

Frontal cortex 0.47 0.12 0.18 0.57 0.00 0.99

Cerebellum 0.50 0.10 0.37 0.24 0.16 0.61

r =correlation coefficient

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Supplemental Table 3. DVR estimates from 1TC, 2TC and MA1

Regions of interest Kinetic Radioligand FTC model BST SN THA VST CAU PUT HIP INS TL PL CER X

1.51 1.79 1.95 2.73 1.77 2.96 1.82 2.31 2.15 2.27 2.17 2.65 1TC 10% 9% 12% 10% 27% 9% 11% 9% 10% 10% 9% 8%

1.47 1.76 1.92 2.65 1.71 2.86 1.82 2.23 2.08 2.17 2.07 2.58 18F-BCPP-EF 2TC 12% 8% 13% 11% 28% 9% 11% 9% 10% 9% 8% 10%

1.58 1.78 1.93 2.67 1.71 2.87 1.83 2.25 2.10 2.19 2.09 2.59 MA1 12% 10% 14% 12% 29% 10% 11% 10% 10% 10% 9% 10%

1.43 1.39 1.26 1.50 0.96 1.66 1.45 1.76 1.60 1.47 1.53 1.88 1TC 18% 21% 14% 14% 24% 14% 17% 15% 16% 15% 14% 19%

1.59 1.44 1.27 1.49 1.04 1.81 1.58 1.87 1.71 1.51 1.52 2.04 11C-SA-5403 2TC 25% 38% 18% 16% 28% 18% 25% 17% 21% 19% 14% 24%

1.34 1.28 1.15 1.36 0.90 1.54 1.36 1.62 1.47 1.33 1.37 1.71 MA1 31% 35% 24% 23% 27% 26% 28% 22% 26% 25% 22% 31%

11C-UCB-J 1TC 1.26 1.50 1.96 3.66 2.17 3.67 2.50 3.63 3.34 3.11 3.07 2.80

7% 8% 13% 8% 24% 7% 10% 9% 8% 11% 10% 8%

1.27 1.49 1.92 3.58 2.09 3.54 2.44 3.51 3.24 3.00 2.95 2.81 2TC 6% 8% 14% 7% 23% 6% 9% 8% 8% 10% 9% 7%

1.28 1.52 1.98 3.63 2.15 3.62 2.53 3.61 3.32 3.08 3.03 2.84 MA1 7% 8% 13% 7% 24% 7% 10% 8% 8% 10% 10% 8%

11 11 *17 values for C-SA-4503 2TC estimation and 3 values for C-UCB-J 2TC estimation were determined as unidentifiable and excluded (based on VT of SE% > 10).

THE JOURNAL OF NUCLEAR MEDICINE • Vol. 61• No. 1 • xxx 2019 Mansur et al. BST: Brainstem, SN: substantia nigra, THA: thalamus, VST: ventral striatum, CAU: caudate, PUT: putamen, HIP: hippocampus, INS: insular cortex, Tl; temporal lobe, PL: parietal lobe, FTCX: frontal cortex, CER: cerebellum

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Supplemental Table 4. VT/fp estimates from 1TC, 2TC and MA1

Kinetic Regions of interest Radioligand model BST SN THA VST CAU PUT HIP INS TL PL FTCX CER CS 143 214 254 278 391 255 422 259 329 306 323 309 377 1TC 16% 17% 14% 21% 20% 35% 18% 18% 17% 17% 18% 18% 15%

157 232 277 302 418 271 451 286 351 328 343 327 405 18F-BCPP-EF 2TC 15% 18% 14% 20% 19% 35% 17% 17% 17% 17% 17% 18% 15%

157 232 277 303 419 271 450 287 352 329 344 329 405 MA1 16% 18% 14% 20% 20% 35% 17% 17% 17% 17% 18% 18% 15%

372 509 488 455 543 354 596 518 630 572 526 553 668 1TC 30% 27% 26% 27% 27% 37% 25% 24% 26% 26% 26% 29% 27%

456 611 544 520 605 476 698 608 736 664 598 628 765 11C-SA-5403 2TC 28% 30% 20% 27% 30% 27% 25% 24% 27% 26% 25% 29% 27%

465 588 553 508 604 405 671 590 714 647 584 614 747 MA1 36% 29% 29% 28% 27% 35% 25% 23% 26% 26% 26% 30% 27%

25 31 37 49 91 54 91 62 90 83 77 76 69 1TC 18% 13% 12% 15% 15% 28% 14% 12% 12% 11% 13% 13% 12%

11C-UCB-J 26 32 39 50 92 55 92 63 91 84 78 77 72 2TC 17% 13% 11% 14% 15% 27% 13% 12% 10% 11% 13% 13% 12%

25 32 38 50 92 54 91 64 91 84 78 76 72 MA1 17% 13% 11% 15% 15% 27% 13% 12% 10% 11% 13% 13% 12%

11 11 *17 values for C-SA-4503 2TC estimation and 3 values for C-UCB-J 2TC estimation were determined as unidentifiable and excluded (based on VT of SE%>10).

THE JOURNAL OF NUCLEAR MEDICINE • Vol. 61• No. 1 • xxx 2019 Mansur et al. CS: centrum semiovale, BST: brainstem, SN: substantia nigra, THA: thalamus, VST: ventral striatum, CAU: caudate,

PUT: putamen, HIP: hippocampus, INS: insular cortex, Tl; temporal lobe, PL: parietal lobe, FTCX: frontal cortex, CER: cerebellum

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Supplemental Table 5. Age effect on DVR

18F-BCPP-EF 11C-SA-4503 11C-UCB-J ROI r p ∆/year r p ∆/year r p ∆/year

Brainstem -0.25 0.43 -0.23 -0.25 0.43 -0.62 -0.5 0.1 -0.28

Substantia nigra 0.03 0.92 0.03 -0.31 0.33 -0.87 -0.24 0.46 -0.15

Thalamus -0.69 0.01* -0.74 -0.42 0.18 -0.79 -0.76 0.004** -0.81

Ventral striatum 0.44 0.16 -0.4 -0.39 0.21 -0.7 -0.81 0.001** -0.50

Caudate -0.73 0.01* -1.7 -0.47 0.12 -1.01 -0.87 0.0002** -1.70

Putamen -0.29 0.35 -0.23 -0.13 0.69 -0.27 -0.46 0.13 -0.26

Hippocampus -0.45 0.14 -0.41 -0.18 0.57 -0.4 -0.59 0.04* -0.46

Insular cortex -0.44 0.15 -0.35 -0.3 0.35 -0.53 -0.5 0.1 -0.34

Temporal lobe -0.44 0.15 -0.36 -0.24 0.44 -0.5 -0.47 0.13 -0.31

Parietal lobe -0.64 0.02* -0.51 -0.28 0.39 -0.54 -0.65 0.02* -0.56

Frontal cortex -0.71 0.01* -0.49 -0.44 0.15 -0.77 -0.68 0.02* -0.54

Cerebellum -0.004 0.99 -0.003 -0.25 0.43 -0.63 0.01 0.98 0.01

18 11 11 DVR results for F-BCPP-EF, C-SA-4503 and C-UCB-J calculated from MA1, MA1 and 1TC-derived VT estimates.

r = correlation coefficient, *p<0.05, **p<0.005

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Supplemental Table 6. Age effect on VT/fp

18F-BCPP-EF 11C-SA-4503 11C-UCB-J ROI r p ∆/year r p ∆/year r p ∆/year

Centrum semiovale -0.22 0.49 -0.27 -0.11 0.74 -0.31 0.23 0.47 0.33

Brainstem -0.35 0.27 -0.5 -0.35 0.26 -0.83 0.04 0.9 0.05

Substantia nigra -0.22 0.5 -0.24 -0.51 0.09 -1.18 0.17 0.59 0.16

Thalamus -0.66 0.02* -1.06 -0.47 0.12 -1.05 -0.4 0.2 -0.47

Ventral striatum -0.44 0.15 -0.69 -0.42 0.17 -0.9 -0.14 0.67 -0.17

Caudate -0.74 0.01* -2.09 -0.47 0.13 -1.3 -0.6 0.04* -1.31

Putamen -0.37 0.24 -0.5 -0.26 0.41 -0.52 0.06 0.86 0.06

Hippocampus -0.51 0.09 -0.7 -0.35 0.26 -0.66 -0.15 0.65 -0.14

Insular cortex -0.45 0.14 -0.63 -0.35 0.27 -0.73 -0.03 0.93 -0.03

Temporal lobe -0.47 0.12 -0.64 -0.35 0.26 -0.73 0.01 0.98 0.01

Parietal lobe -0.57 0.05* -0.81 -0.38 0.22 -0.78 -0.23 0.47 -0.24

Frontal cortex -0.54 0.07 -0.79 -0.4 0.2 -0.96 -0.22 0.5 -0.22

Cerebellum -0.21 0.52 -0.25 -0.38 0.23 -0.82 0.32 0.31 0.31

18 11 11 VT/fp results for F-BCPP-EF, C-SA-4503 and C-UCB-J calculated from MA1, MA1 and 1TC-derived VT estimates.

r = correlation coefficient, *p<0.05, **p<0.005

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Supplemental Table 7. Age effects on VT with regional volume as covariate

18F-BCPP-EF 11C-SA-4503 11C-UCB-J ROI r p r p r p

Centrum semiovale -0.10 0.77 -0.01 0.99 -0.10 0.77

Brainstem -0.24 0.48 -0.22 0.52 -0.56 0.08

Substantia nigra 0.17 0.62 -0.37 0.27 -0.18 0.61

Thalamus -0.50 0.11 -0.31 0.36 -0.76 0.01*

Ventral striatum -0.18 0.59 -0.20 0.55 -0.61 0.05*

Caudate -0.63 0.04* -0.26 0.44 -0.78 0.004**

Putamen -0.02 0.94 0.03 0.94 -0.34 0.31

Hippocampus -0.11 0.74 0.02 0.95 -0.49 0.13

Insular cortex -0.13 0.71 -0.20 0.56 -0.60 0.05

Temporal lobe 0.23 0.51 0.23 0.50 -0.36 0.28

Parietal lobe -0.27 0.43 0.25 0.45 -0.66 0.03*

Frontal cortex 0.13 0.71 0.16 0.64 -0.40 0.22

Cerebellum 0.22 0.51 -0.05 0.89 -0.06 0.85

r = correlation coefficient

*p<0.05, **p<0.005

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