Synthesis and evaluation of radioligands for imaging brain nociceptin/orphanin FQ peptide (NOP) receptors with positron emission tomography

Article abstract of DOI:10.1021/jm101487v

Positron emission tomography (PET) coupled to an effective radioligand could provide an important tool for understanding possible links between neuropsychiatric disorders and brain NOP (nociceptin/orphanin FQ peptide) receptors. We sought to develop such a PET radioligand. High-affinity NOP ligands were synthesized based on a 3-(2′-fluoro-4′,5′- dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)-2(2-halobenzyl) -N-alkylpropanamide scaffold and from experimental screens in rats, with ex vivo LC-MS/MS measures, three ligands were identified for labeling with carbon-11 and evaluation with PET in monkey. Each ligand was labeled by ¹¹C-methylation of an N-desmethyl precursor and studied in monkey under baseline and NOP receptor-preblock conditions. The three radioligands, [¹¹C](S)-10a-c, gave similar results. Baseline scans showed high entry of radioactivity into the brain to give a distribution reflecting that expected for NOP receptors. Preblock experiments showed high early peak levels of brain radioactivity, which rapidly declined to a much lower level than seen in baseline scans, thereby indicating a high level of receptor-specific binding in baseline experiments. Overall, [¹¹C](S)-10c showed the most favorable receptor-specific signal and kinetics and is now selected for evaluation in human subjects.

Full text of DOI:10.1021/jm101487v

Supporting Information.
Synthesis and Evaluation of Radioligands for Imaging Brain
Nociceptin/Orphanin FQ Peptide (NOP) Receptors with Positron Emission
Tomography
Victor W. Pike , Karen S. Rash, Zhaogen Chen, Concepción Pedregal, Michael A. Statnick,
Yasuyuki Kimura, Jinsoo Hong, Sami S. Zoghbi, Masahiro Fujita, Miguel A. Toledo, Nuria Diaz,
Susan L. Gackenheimer, Johannes T. Tauscher, Vanessa N. Barth, Robert B. Innis
Table of Contents
X-ray crystallographic determination of the absolute configuration of the biologically more
active enantiomer of 9c
S2
X-ray crystallographic determination of the absolute configuration of the biologically less
active enantiomer of 9a
S12
Separation of [11C](S)-10c with HPLC
S27
S28
S29
S30
S31
S32
S33
S34
S34
Analysis of [11C](S)-10a with radio-HPLC
Analysis of [11C](S)-10b with radio-HPLC
Analysis of [11C](S)-10c with radio-HPLC
Analysis of [11C](S)-10c with chiral radio-HPLC
Displacement of [11C](S)-10c from monkey brain with 1
Attempted displacement of [11C](S)-10c from monkey brain with naloxone
Brain baseline and pre-block time-activity curves in monkey injected with [11C](R)-10c
References
S1

X-ray crystallographic determination of the absolute configuration of the
biologically more active enantiomer of 9c
Sample Preparation
Single crystals were grown by slow evaporation of a solution of the biologically more active
enantiomer of 9c in ethanol/water (50/50, v/v).
Description of Crystal Structure
A single crystal was mounted on a thin fiber at −173 °C. Data were collected using a CuK
α
radiation source (λ = 1.54178 Å) and a Bruker D8 based 3-circle goniometer diffractometer
equipped with a SMART 6000CCD area detector1. Cell refinement and data reduction were
performed using the SAINT program V7.68A2. The unit cell was indexed, having orthorhombic
parameters of a = 7.4629(2) Å, b = 9.80302(2) Å, and c = 27.7482(5) Å. The cell volume of crystal
3
3
structure was 2030.03(8) Å . The calculated density of the structure is 1.330 g/cm at −173 °C.
The structure was solved by direct methods2. All atomic parameters were independently refined.
The space group choice, that is P212121, was confirmed by successful convergence of the full-
2
matrix least-squares refinement on F (refernce 3) with a final goodness of fit of 1.035. The final
residual factor, R , was = 0.0390 and the largest difference peak and hole after the final refinement
1
-3
cycle were 0.174 and −0.258 (e.A ), respectively. The absolute stereochemistry was determined by
refinement of the absolute structure parameter to 0.01(2), indicating the stereochemistry of the
molecule depicted4.
Conclusion
A single crystal structure was obtained and showed the stereocenter to possess the S configuration
by using the anomalous scattering contribution of the heavy atom (sulfur). A thermal ellipsoid
representation of 9c is shown at –173 °C in Figure S1. A photomicrograph shows that the
morphology of the single crystals was bladed (Figure S2).
S2

Figure S1. Thermal ellipsoid representation of biologically active enantiomer of 9c, showing S-
configuration.
S3

Figure S2. Photomicrograph of crystals of (S)-9c.
S4

Table S1. Crystal data and structure refinement for (S)-9c.
Identification code
Empirical formula
Formula weight
Temperature
10022_0m
C21H24F2N2 O2S
406.48
100(2) K
Wavelength
1.54178 Å
Crystal system
Space group
Orthorhombic
P2(1)2(1)2(1)
a = 7.4629(2) Å
b = 9.8030(2) Å
c = 27.7482(5) Å
Unit cell dimensions
α= 90°.
β= 90°.
γ = 90°.
3
Volume
2030.03(8) Å
4
Z
3
Density (calculated)
Absorption coefficient
F(000)
1.330 Mg/m
-1
1.739 mm
856
3
Crystal size
0.15 x 0.08 x 0.01 mm
3.19 to 71.99°.
Theta range for data collection
Index ranges
-8<=h<=5, -10<=k<=11, -33<=l<=30
Reflections collected
Independent reflections
Completeness to theta = 71.99°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
8471
3589 [R(int) = 0.0333]
92.8 %
None
0.9828 and 0.7805
2
Full-matrix least-squares on F
3589 / 0 / 262
2
Goodness-of-fit on F
1.035
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0390, wR2 = 0.0974
R1 = 0.0467, wR2 = 0.1031
0.01(2)
Absolute structure parameter
Largest diff. peak and hole
-3
0.174 and -0.258 e.Å
S5

4
2
Table S2. Atomic coordinates (× 10 ) and equivalent isotropic displacement parameters (Å ×
3
ij
10 ) for 10022_0m. U(eq) is defined as one third of the trace of the orthogonalized U tensor.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
S(1)
C(2)
O(4)
C(7)
C(3)
C(9)
C(8)
C(5)
7684(1)
9774(3)
11841(2)
11126(3)
9984(3)
8704(4)
10491(4)
13107(4)
13035(4)
7659(2)
8196(3)
8915(3)
9397(4)
8927(3)
9359(4)
6291(4)
7950(3)
4726(4)
4126(2)
4103(3)
5928(4)
4589(4)
2190(4)
1587(4)
5125(4)
3981(4)
2773(4)
6901(2)
702(1)
576(3)
482(2)
779(3)
263(3)
1016(3)
1038(3)
-84(3)
593(1)
863(1)
1520(1)
543(1)
1390(1)
45(1)
66(1)
1180(1)
705(1)
-345(1)
2290(1)
2232(1)
1507(1)
1704(1)
2044(1)
3012(1)
2798(1)
2671(1)
2619(1)
2429(1)
3514(1)
3807(1)
4373(1)
4101(1)
4087(1)
4370(1)
3821(1)
4093(1)
34(1)
31(1)
32(1)
34(1)
30(1)
34(1)
34(1)
36(1)
37(1)
40(1)
30(1)
31(1)
32(1)
30(1)
31(1)
32(1)
33(1)
31(1)
36(1)
33(1)
36(1)
32(1)
46(1)
46(1)
37(1)
44(1)
41(1)
49(1)
C(6)
F(9)
665(3)
1176(2)
-516(2)
858(2)
N(12)
C(13)
C(10)
C(14)
C(11)
C(16)
C(15)
C(17)
O(17)
N(18)
C(19)
C(20)
C(23)
C(24)
C(21)
C(22)
C(25)
F(21)
-1198(2)
1261(3)
-1492(2)
-169(3)
-859(3)
-429(2)
-1586(2)
655(2)
-766(3)
42(3)
1543(3)
466(3)
1132(3)
1893(3)
-276(3)
1470(2)
________________________________________________________________________________
S6

Table S3. Bond lengths [Å] and angles [°] for 10022_0m.
Bond lengths
S(1)-C(9)
S(1)-C(2)
C(2)-C(7)
C(2)-C(3)
O(4)-C(5)
O(4)-C(3)
C(7)-C(8)
C(7)-C(6)
C(3)-C(14)
C(3)-C(10)
C(9)-C(8)
C(9)-F(9)
C(5)-C(6)
N(12)-C(13)
N(12)-C(11)
N(12)-C(15)
C(13)-C(14)
C(10)-C(11)
C(16)-C(17)
C(16)-C(15)
C(16)-C(19)
C(17)-O(17)
C(17)-N(18)
C(19)-C(20)
C(20)-C(21)
C(20)-C(25)
C(23)-C(24)
C(23)-C(22)
C(24)-C(25)
C(21)-F(21)
C(21)-C(22)
Angles
C(9)-S(1)-C(2)
C(7)-C(2)-C(3)
C(7)-C(2)-S(1)
C(3)-C(2)-S(1)
C(5)-O(4)-C(3)
C(2)-C(7)-C(8)
C(2)-C(7)-C(6)
C(8)-C(7)-C(6)
1.727(3)
1.735(3)
1.359(4)
1.504(4)
1.446(3)
1.447(3)
1.428(4)
1.499(4)
1.528(3)
1.533(3)
1.335(4)
1.343(3)
1.509(4)
1.458(3)
1.461(3)
1.460(3)
1.518(3)
1.518(3)
1.524(4)
1.531(4)
1.535(3)
1.228(3)
1.340(3)
1.512(4)
1.380(4)
1.391(4)
1.375(5)
1.379(5)
1.383(4)
1.366(3)
1.380(4)
89.79(12)
126.1(2)
112.02(19)
121.91(19)
114.03(18)
112.7(2)
119.9(2)
127.4(2)
108.1(2)
104.97(19)
111.7(2)
111.1(2)
111.5(2)
109.3(2)
127.8(2)
113.9(2)
118.24(19)
111.6(2)
111.0(2)
109.4(2)
109.58(19)
111.40(19)
111.97(19)
110.4(2)
112.9(2)
112.7(2)
110.2(2)
107.8(2)
111.3(2)
109.1(2)
112.0(2)
123.2(2)
120.4(2)
116.4(2)
113.9(2)
116.1(3)
121.1(2)
122.8(2)
120.3(3)
120.2(3)
118.4(2)
117.5(3)
124.1(3)
117.9(3)
121.4(3)
O(4)-C(3)-C(2)
O(4)-C(3)-C(14)
C(2)-C(3)-C(14)
O(4)-C(3)-C(10)
C(2)-C(3)-C(10)
C(14)-C(3)-C(10)
C(8)-C(9)-F(9)
C(8)-C(9)-S(1)
F(9)-C(9)-S(1)
C(9)-C(8)-C(7)
O(4)-C(5)-C(6)
C(7)-C(6)-C(5)
C(13)-N(12)-C(11)
C(13)-N(12)-C(15)
C(11)-N(12)-C(15)
N(12)-C(13)-C(14)
C(11)-C(10)-C(3)
C(13)-C(14)-C(3)
N(12)-C(11)-C(10)
C(17)-C(16)-C(15)
C(17)-C(16)-C(19)
C(15)-C(16)-C(19)
N(12)-C(15)-C(16)
O(17)-C(17)-N(18)
O(17)-C(17)-C(16)
N(18)-C(17)-C(16)
C(20)-C(19)-C(16)
C(21)-C(20)-C(25)
C(21)-C(20)-C(19)
C(25)-C(20)-C(19)
C(24)-C(23)-C(22)
C(23)-C(24)-C(25)
F(21)-C(21)-C(20)
F(21)-C(21)-C(22)
C(20)-C(21)-C(22)
C(23)-C(22)-C(21)
C(24)-C(25)-C(20)
Symmetry transformations used to generate equivalent atoms:
S7

2
3
Table S4. Anisotropic displacement parameters (Å × 10 ) for 10022_0m. The anisotropic
2
2 2 11
12
displacement factor exponent takes the form: -2π [ h a* U + ... + 2 h k a* b* U ].
______________________________________________________________________________
11
U
22
U
33
U
23
U
13
U
12
U
______________________________________________________________________________
S(1)
C(2)
O(4)
C(7)
C(3)
C(9)
C(8)
C(5)
27(1)
23(1)
25(1)
28(1)
23(2)
36(2)
30(2)
25(2)
27(2)
40(1)
29(1)
31(2)
28(2)
25(1)
28(2)
32(2)
30(2)
28(2)
34(1)
30(1)
38(2)
32(2)
50(2)
32(2)
37(2)
56(2)
41(2)
39(1)
42(1)
31(1)
37(1)
35(1)
32(1)
34(1)
40(1)
40(1)
44(2)
49(1)
30(1)
26(1)
30(1)
30(1)
28(1)
33(1)
33(1)
31(1)
31(1)
31(1)
40(1)
36(1)
48(2)
59(2)
34(1)
36(1)
42(2)
43(1)
33(1)
39(1)
34(1)
38(1)
34(1)
31(1)
33(1)
41(1)
40(1)
33(1)
31(1)
36(1)
37(1)
37(1)
38(1)
30(1)
36(1)
33(1)
44(1)
37(1)
31(1)
29(1)
38(1)
48(2)
40(1)
39(1)
40(1)
64(1)
2(1)
0(1)
-2(1)
-2(1)
-2(1)
0(1)
-3(1)
-3(1)
-4(1)
0(1)
1(1)
-2(1)
-4(1)
-1(1)
0(1)
2(1)
1(1)
1(1)
1(1)
2(1)
4(1)
6(1)
7(1)
13(1)
9(1)
-1(1)
2(1)
3(1)
-2(1)
0(1)
1(1)
1(1)
0(1)
0(1)
2(1)
-1(1)
1(1)
3(1)
1(1)
4(1)
0(1)
0(1)
2(1)
0(1)
1(1)
1(1)
-1(1)
0(1)
-2(1)
-1(1)
4(1)
-1(1)
16(1)
5(1)
-2(1)
5(1)
-4(1)
-10(1)
-2(1)
0(1)
-4(1)
-2(1)
5(1)
0(1)
C(6)
F(9)
-1(1)
-8(1)
-2(1)
-3(1)
-1(1)
-2(1)
-3(1)
-1(1)
-6(1)
3(1)
-4(1)
-4(1)
0(1)
-2(1)
8(1)
N(12)
C(13)
C(10)
C(14)
C(11)
C(16)
C(15)
C(17)
O(17)
N(18)
C(19)
C(20)
C(23)
C(24)
C(21)
C(22)
C(25)
F(21)
0(1)
-1(1)
-3(1)
-7(1)
-6(1)
______________________________________________________________________________
S8

4
2
3
Table S5. Hydrogen coordinates (× 10 ) and isotropic displacement parameters (Å × 10 )
for 10022_0m.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
H(8)
11247
12831
14332
13558
13744
10151
8173
8187
10229
9457
7677
8914
10588
6506
9023
7829
5478
7072
1370
353
4412
2338
3260(30)
4610(40)
1204
-1060
-21
1587
166
-204
1126
1315
743
41
43
43
45
45
37
37
38
38
37
37
38
38
38
39
39
43
43
55
56
52
49
13(6)
29(7)
H(5A)
H(5B)
H(6A)
H(6B)
H(13A)
H(13B)
H(10A)
H(10B)
H(14A)
H(14B)
H(11A)
H(11B)
H(16)
H(15A)
H(15B)
H(19A)
H(19B)
H(23)
H(24)
H(22)
H(25)
H(18A)
H(18B)
461
893
2362
2417
1372
1349
1672
1586
2100
2176
3039
2981
2830
3477
3694
4565
4104
4557
3635
2200(8)
2434(10)
1511
-1354
-1845
2182
1306
-2430
-1428
834
-573
-1861
-1710
-811
2049
230
2636
-1019
480(20)
1470(30)
________________________________________________________________________________
S9

Table S6. Torsion angles [°] for 10022_0m.
________________________________________________________________
C(9)-S(1)-C(2)-C(7)
C(9)-S(1)-C(2)-C(3)
C(3)-C(2)-C(7)-C(8)
S(1)-C(2)-C(7)-C(8)
0.5(2)
-179.0(2)
179.2(2)
-0.3(3)
C(3)-C(2)-C(7)-C(6)
S(1)-C(2)-C(7)-C(6)
1.5(4)
-178.02(19)
-44.9(3)
-164.3(2)
77.7(2)
C(5)-O(4)-C(3)-C(2)
C(5)-O(4)-C(3)-C(14)
C(5)-O(4)-C(3)-C(10)
C(7)-C(2)-C(3)-O(4)
S(1)-C(2)-C(3)-O(4)
C(7)-C(2)-C(3)-C(14)
S(1)-C(2)-C(3)-C(14)
C(7)-C(2)-C(3)-C(10)
S(1)-C(2)-C(3)-C(10)
C(2)-S(1)-C(9)-C(8)
11.2(3)
-169.35(16)
126.2(3)
-54.3(3)
-111.2(3)
68.3(3)
-0.6(2)
C(2)-S(1)-C(9)-F(9)
F(9)-C(9)-C(8)-C(7)
S(1)-C(9)-C(8)-C(7)
177.9(2)
-177.8(2)
0.5(3)
C(2)-C(7)-C(8)-C(9)
C(6)-C(7)-C(8)-C(9)
C(3)-O(4)-C(5)-C(6)
C(2)-C(7)-C(6)-C(5)
C(8)-C(7)-C(6)-C(5)
O(4)-C(5)-C(6)-C(7)
C(11)-N(12)-C(13)-C(14)
C(15)-N(12)-C(13)-C(14)
O(4)-C(3)-C(10)-C(11)
C(2)-C(3)-C(10)-C(11)
C(14)-C(3)-C(10)-C(11)
N(12)-C(13)-C(14)-C(3)
O(4)-C(3)-C(14)-C(13)
C(2)-C(3)-C(14)-C(13)
C(10)-C(3)-C(14)-C(13)
C(13)-N(12)-C(11)-C(10)
C(15)-N(12)-C(11)-C(10)
C(3)-C(10)-C(11)-N(12)
C(13)-N(12)-C(15)-C(16)
C(11)-N(12)-C(15)-C(16)
C(17)-C(16)-C(15)-N(12)
C(19)-C(16)-C(15)-N(12)
C(15)-C(16)-C(17)-O(17)
C(19)-C(16)-C(17)-O(17)
-0.1(3)
177.4(3)
67.7(3)
17.2(3)
-160.1(3)
-49.4(3)
63.0(3)
-172.5(2)
66.9(3)
-172.5(2)
-48.5(3)
-56.8(3)
-70.7(2)
172.4(2)
48.6(3)
-62.8(3)
173.1(2)
56.4(3)
76.3(3)
-160.6(2)
49.2(3)
170.1(2)
67.5(3)
-52.1(3)
S10

C(15)-C(16)-C(17)-N(18)
C(19)-C(16)-C(17)-N(18)
C(17)-C(16)-C(19)-C(20)
C(15)-C(16)-C(19)-C(20)
C(16)-C(19)-C(20)-C(21)
C(16)-C(19)-C(20)-C(25)
C(22)-C(23)-C(24)-C(25)
C(25)-C(20)-C(21)-F(21)
C(19)-C(20)-C(21)-F(21)
C(25)-C(20)-C(21)-C(22)
C(19)-C(20)-C(21)-C(22)
C(24)-C(23)-C(22)-C(21)
F(21)-C(21)-C(22)-C(23)
C(20)-C(21)-C(22)-C(23)
C(23)-C(24)-C(25)-C(20)
C(21)-C(20)-C(25)-C(24)
C(19)-C(20)-C(25)-C(24)
-110.6(2)
129.8(2)
-74.1(3)
167.1(2)
-86.7(3)
94.8(3)
0.0(4)
178.8(2)
0.1(4)
0.0(4)
-178.6(2)
0.0(4)
-178.8(2)
0.0(4)
-0.1(4)
0.1(4)
178.7(3)
________________________________________________________________
Symmetry transformations used to generate equivalent atoms:
S11

X-Ray crystallographic determination of the absolute configuration of the
biologically less active enantiomer of 9a
Sample Preparation
Single crystals were grown by adding approximately 50 mg of the biologically less active
enantiomer of 9a to a small vial. To the vial, approximately of water-saturated ethyl acetate
(0.75mL) was added to dissolve the compound. The sample was set aside to evaporate. Large
single crystals grew on the side of the vial as the sample evaporated to dryness. The single crystals
were isolated and a sample was isolated for single crystal analysis.
Description of Crystal Structure
A single crystal was mounted on a thin fiber at −173 °C. Data were collected using a CuK
α
radiation source (λ = 1.54178 Å) and a Bruker D8 based 3-circle goniometer diffractometer
equipped with a SMART 6000CCD area detector1. Cell refinement and data reduction were
performed using the SAINT program V7.68°.2 The unit cell was indexed, having monoclinic
parameters of a = 9.9155(8) Å, b = 19.9332(16) Å, and c = 11.6883(10) Å and β = 95.439(3)°. The
3
cell volume of crystal structure was 2299.8(3) Å . The calculated density of the structure is 1.293
g/cm3 at −173 °C. The structure was solved by direct methods.2 All atomic parameters were
independently refined. The chiral space group choice, that is P21, was confirmed by successful
2
convergence of the full-matrix least-squares refinement on F (reference 3) with a final goodness of
fit of 1.027. The final residual factor, R , was = 0.0534 and the largest difference peak and hole
1
-3
after the final refinement cycle were 0.381 and -0.265 (e.A ), respectively. The absolute
stereochemistry was determined by refinement of the absolute structure parameter to -0.02(3),
indicating the stereochemistry of the molecule depicted.4
Conclusion
A single crystal structure has been obtained and shows the stereocenter to possess the R
configuration by using the anomalous scattering contribution of the heavy atom (sulfur) and
S12

refinement of its absolute structure parameter that resulted in a value of -0.02(2). A thermal
ellipsoid representation of 9a is shown at – 173 °C in Figure S3.
Figure S3. Thermal ellipsoid representation of biologically less active enantiomer of 9a, showing
R-configuration
S13

Table S7. Crystal data and structure refinement for 09061_0m (lot V19E0077172-027).
Identification code
Empirical formula
Formula weight
Temperature
09061_0m
C24H30F2N2O2S
448.56
100(2) K
Wavelength
1.54178 Å
Crystal system
Space group
Monoclinic
P2(1)
Unit cell dimensions
a = 9.9155(8) Å
b = 19.9332(16) Å
c = 11.6883(10) Å
α = 90°.
β = 95.439(3)°.
γ = 90°.
3
Volume
2299.8(3) Å
4
Z
3
Density (calculated)
Absorption coefficient
F(000)
1.296 Mg/m
-1
1.582 mm
952
3
Crystal size
0.20 x 0.05 x 0.05 mm
10.54 to 58.63°.
Theta range for data collection
Index ranges
-10<=h<=10, -21<=k<=21, -12<=l<=12
Reflections collected
Independent reflections
Completeness to theta = 58.63°
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
9779
5642 [R(int) = 0.0763]
95.9 %
None
0.9251 and 0.7426
2
Full-matrix least-squares on F
5642 / 1 / 564
2
Goodness-of-fit on F
1.036
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0525, wR2 = 0.1246
R1 = 0.0710, wR2 = 0.1365
-0.02(2)
Absolute structure parameter
Largest diff. peak and hole
-3
0.381 and -0.265 e.Å
S14

4
2
Table S8. Atomic coordinates (× 10 ) and equivalent isotropic displacement parameters (Å ×
3
ij
10 ) for 09061_0m. U(eq) is defined as one third of the trace of the orthogonalized U tensor.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
S(1A)
4363(1)
-155(1)
1562(3)
-790(3)
4016(3)
258(4)
6453(1)
5020(1)
9438(2)
6833(2)
7620(2)
3842(2)
7034(2)
4393(2)
1980(2)
4053(2)
7288(2)
4229(3)
4578(2)
2234(2)
6766(2)
4491(3)
7181(3)
8996(3)
5364(3)
3067(3)
6951(3)
3361(3)
5616(3)
3580(3)
6614(3)
7864(3)
6570(3)
7307(3)
5052(3)
3525(3)
6626(3)
4855(3)
5905(3)
7152(3)
3837(1)
5688(1)
10111(3)
4172(3)
4850(3)
4754(3)
9802(3)
-374(3)
683(3)
41(1)
45(1)
50(1)
40(1)
53(1)
63(1)
41(1)
58(1)
33(1)
35(1)
36(1)
38(1)
41(1)
44(1)
34(1)
48(1)
36(1)
39(1)
44(1)
42(1)
39(1)
37(1)
47(1)
41(1)
40(1)
39(1)
44(1)
39(1)
35(1)
40(1)
38(1)
38(1)
39(1)
38(1)
S(1B)
F(19B)
O(7B)
F(2A)
F(2B)
O(24B)
F(19A)
N(25A)
N(12A)
N(12B)
C(13A)
O(7A)
O(24A)
N(25B)
C(2B)
-1337(3)
3106(3)
4241(4)
5309(4)
-851(4)
6240(4)
4255(3)
6465(3)
829(4)
2566(3)
7111(4)
3587(5)
5146(3)
997(3)
9550(4)
4539(5)
9462(4)
10991(5)
6673(5)
-1843(5)
5000(5)
2259(5)
8847(5)
114(5)
-28(5)
C(24B)
C(19B)
C(5A)
-225(4)
1448(5)
3997(5)
4677(5)
4098(4)
5563(5)
620(5)
C(23A)
C(2A)
C(15A)
C(27B)
C(17A)
C(3A)
5395(5)
3980(4)
-42(5)
5970(5)
8932(5)
3160(4)
6447(5)
4280(4)
-993(5)
5912(5)
3212(4)
5779(5)
6319(5)
C(16B)
C(6B)
-1564(5)
346(4)
C(11B)
C(8A)
4556(4)
4474(5)
542(5)
C(18A)
C(10B)
C(10A)
C(4A)
3628(5)
4091(4)
-2062(4)
C(13B)
S15

C(21B)
C(11A)
C(22A)
C(20A)
C(9A)
2173(5)
3885(5)
3771(5)
2431(5)
4314(4)
3331(5)
6027(4)
3419(5)
2648(5)
5261(5)
-501(4)
4443(5)
4765(5)
745(5)
8636(3)
4143(3)
3008(3)
3886(3)
5740(3)
3932(3)
4944(3)
846(3)
12875(5)
2830(5)
-2831(5)
-2141(5)
4709(4)
-1186(4)
3966(4)
1004(6)
-2971(5)
909(4)
46(1)
37(1)
44(1)
44(1)
35(1)
40(1)
39(1)
56(2)
46(1)
35(1)
36(1)
39(1)
42(1)
38(1)
38(1)
46(1)
37(1)
47(1)
45(1)
35(1)
41(1)
59(2)
40(1)
40(1)
46(1)
51(1)
55(2)
38(1)
C(19A)
C(14A)
C(28A)
C(21A)
C(24A)
C(9B)
3418(3)
2413(3)
5686(3)
1269(3)
4768(3)
6060(3)
3147(3)
4785(3)
6465(3)
9082(3)
5982(3)
6392(3)
7888(3)
1154(3)
8493(3)
8427(3)
8052(3)
8115(3)
5881(4)
5488(3)
4734(4)
454(5)
C(26A)
C(6A)
6285(4)
9884(4)
1064(5)
3517(5)
5799(4)
11985(5)
2693(5)
5143(4)
7791(5)
-832(6)
10826(5)
9715(5)
11732(5)
12749(5)
10726(5)
3636(4)
C(26B)
C(16A)
C(3B)
4912(5)
-234(5)
-1970(4)
2261(5)
-833(5)
-702(4)
-965(5)
4365(6)
478(5)
C(14B)
C(20B)
C(5B)
C(8B)
C(15B)
C(27A)
C(18B)
C(17B)
C(23B)
C(22B)
C(28B)
C(4B)
-421(5)
419(5)
1263(6)
1952(5)
-514(4)
________________________________________________________________________________
S16

Table S9. Bond lengths [Å] and angles [°] for 09061_0m. (Symmetry transformations used to
generate equivalent atoms)
Bond lengths
Bond angles
S(1A)-C(2A)
S(1A)-C(9A)
S(1B)-C(2B)
S(1B)-C(9B)
F(19B)-C(19B)
O(7B)-C(8B)
O(7B)-C(6B)
F(2A)-C(2A)
F(2B)-C(2B)
O(24B)-C(24B)
F(19A)-C(19A)
N(25A)-C(24A)
N(25A)-C(26A)
N(12A)-C(15A)
N(12A)-C(13A)
N(12A)-C(11A)
N(12B)-C(15B)
N(12B)-C(13B)
N(12B)-C(11B)
C(13A)-C(14A)
O(7A)-C(6A)
O(7A)-C(8A)
O(24A)-C(24A)
N(25B)-C(24B)
N(25B)-C(26B)
C(2B)-C(3B)
1.722(6)
1.753(5)
1.721(6)
1.746(5)
1.367(6)
1.432(6)
1.446(7)
1.348(6)
1.342(7)
1.242(6)
1.354(7)
1.336(7)
1.459(7)
1.455(7)
1.481(7)
1.484(6)
1.448(7)
1.470(7)
1.478(6)
1.512(8)
1.430(7)
1.435(6)
1.241(6)
1.329(6)
1.465(7)
1.329(9)
1.514(8)
1.361(8)
1.389(7)
1.504(8)
1.510(8)
1.378(8)
1.399(8)
1.332(8)
1.542(8)
1.497(8)
1.515(8)
1.520(8)
1.437(8)
1.517(8)
1.545(8)
1.507(8)
1.516(8)
1.488(8)
1.530(7)
1.552(7)
1.395(7)
C(2A)-S(1A)-C(9A)
C(2B)-S(1B)-C(9B)
C(8B)-O(7B)-C(6B)
89.6(3)
89.5(3)
114.4(4)
C(24A)-N(25A)-C(26A) 123.2(4)
C(15A)-N(12A)-C(13A) 108.3(4)
C(15A)-N(12A)-C(11A) 110.9(4)
C(13A)-N(12A)-C(11A) 109.7(4)
C(15B)-N(12B)-C(13B) 113.3(4)
C(15B)-N(12B)-C(11B) 112.0(4)
C(13B)-N(12B)-C(11B) 108.8(4)
N(12A)-C(13A)-C(14A) 111.4(4)
C(6A)-O(7A)-C(8A)
C(24B)-N(25B)-C(26B) 123.7(4)
113.8(4)
C(3B)-C(2B)-F(2B)
C(3B)-C(2B)-S(1B)
F(2B)-C(2B)-S(1B)
O(24B)-C(24B)-N(25B) 122.9(5)
O(24B)-C(24B)-C(16B) 119.2(4)
N(25B)-C(24B)-C(16B) 117.9(4)
C(20B)-C(19B)-F(19B) 118.5(4)
C(20B)-C(19B)-C(18B) 123.8(5)
F(19B)-C(19B)-C(18B) 117.7(4)
127.2(6)
114.5(4)
118.3(4)
C(6A)-C(5A)-C(4A)
C(18A)-C(23A)-C(22A) 121.7(5)
106.8(4)
C(3A)-C(2A)-F(2A)
C(3A)-C(2A)-S(1A)
F(2A)-C(2A)-S(1A)
N(12A)-C(15A)-C(16A) 114.7(4)
C(18A)-C(17A)-C(16A) 112.1(4)
126.9(5)
114.4(4)
118.7(4)
C(24B)-C(16B)
C(19B)-C(20B)
C(19B)-C(18B)
C(5A)-C(6A)
C(2A)-C(3A)-C(4A)
110.4(5)
C(5A)-C(4A)
C(24B)-C(16B)-C(17B) 111.8(4)
C(24B)-C(16B)-C(15B) 107.3(4)
C(17B)-C(16B)-C(15B) 109.7(4)
O(7B)-C(6B)-C(5B)
N(12B)-C(11B)-C(10B) 109.5(4)
O(7A)-C(8A)-C(9A)
O(7A)-C(8A)-C(10A)
C(9A)-C(8A)-C(10A)
O(7A)-C(8A)-C(14A)
C(9A)-C(8A)-C(14A)
C(10A)-C(8A)-C(14A) 106.1(4)
C(23A)-C(18A)-C(19A) 116.2(5)
C(23A)-C(18A)-C(17A) 123.1(5)
C(19A)-C(18A)-C(17A) 120.6(5)
C(11B)-C(10B)-C(8B) 112.9(4)
C(11A)-C(10A)-C(8A) 112.0(4)
C(23A)-C(18A)
C(23A)-C(22A)
C(2A)-C(3A)
C(15A)-C(16A)
C(27B)-C(26B)
C(17A)-C(18A)
C(17A)-C(16A)
C(3A)-C(4A)
C(16B)-C(17B)
C(16B)-C(15B)
C(6B)-C(5B)
C(11B)-C(10B)
C(8A)-C(9A)
110.0(4)
108.5(4)
104.9(4)
114.0(4)
109.8(4)
113.1(4)
C(8A)-C(10A)
C(8A)-C(14A)
C(18A)-C(19A)
C(9A)-C(4A)-C(3A)
114.3(5)
S17

C(10B)-C(8B)
C(10A)-C(11A)
C(4A)-C(9A)
1.529(7)
1.516(7)
1.332(7)
1.506(8)
1.374(8)
1.377(8)
1.379(8)
1.365(8)
1.378(8)
1.511(8)
1.519(8)
1.341(7)
1.506(8)
1.516(9)
1.518(7)
1.438(8)
1.541(7)
1.489(8)
1.382(8)
1.510(8)
1.393(8)
C(9A)-C(4A)-C(5A)
C(3A)-C(4A)-C(5A)
120.0(5)
125.7(5)
N(12B)-C(13B)-C(14B) 110.1(4)
C(22B)-C(21B)-C(20B) 119.7(5)
N(12A)-C(11A)-C(10A) 111.4(4)
C(21A)-C(22A)-C(23A) 119.7(5)
C(19A)-C(20A)-C(21A) 119.2(5)
C(4A)-C(9A)-C(8A)
C(4A)-C(9A)-S(1A)
C(8A)-C(9A)-S(1A)
F(19A)-C(19A)-C(20A) 118.7(4)
F(19A)-C(19A)-C(18A) 117.9(5)
C(20A)-C(19A)-C(18A) 123.4(5)
C(13A)-C(14A)-C(8A) 111.1(4)
C(20A)-C(21A)-C(22A) 119.8(5)
O(24A)-C(24A)-N(25A) 122.4(5)
O(24A)-C(24A)-C(16A) 119.7(4)
N(25A)-C(24A)-C(16A) 117.9(4)
C(13B)-C(14B)
C(21B)-C(22B)
C(21B)-C(20B)
C(22A)-C(21A)
C(20A)-C(19A)
C(20A)-C(21A)
C(28A)-C(26A)
C(24A)-C(16A)
C(9B)-C(4B)
126.2(5)
111.2(4)
122.5(4)
C(9B)-C(8B)
C(26A)-C(27A)
C(26B)-C(28B)
C(3B)-C(4B)
C(14B)-C(8B)
C(5B)-C(4B)
C(18B)-C(23B)
C(18B)-C(17B)
C(23B)-C(22B)
C(4B)-C(9B)-C(8B)
C(4B)-C(9B)-S(1B)
C(8B)-C(9B)-S(1B)
126.0(5)
111.8(4)
122.1(4)
N(25A)-C(26A)-C(28A) 110.8(4)
N(25A)-C(26A)-C(27A) 109.5(4)
C(28A)-C(26A)-C(27A) 111.3(5)
O(7A)-C(6A)-C(5A)
110.2(4)
N(25B)-C(26B)-C(27B) 110.8(4)
N(25B)-C(26B)-C(28B) 109.7(5)
C(27B)-C(26B)-C(28B) 112.7(5)
C(17A)-C(16A)-C(24A) 111.6(4)
C(17A)-C(16A)-C(15A) 111.8(4)
C(24A)-C(16A)-C(15A) 107.1(4)
C(2B)-C(3B)-C(4B)
111.0(5)
C(13B)-C(14B)-C(8B) 111.7(4)
C(19B)-C(20B)-C(21B) 119.2(5)
C(4B)-C(5B)-C(6B)
O(7B)-C(8B)-C(9B)
O(7B)-C(8B)-C(10B)
C(9B)-C(8B)-C(10B)
O(7B)-C(8B)-C(14B)
C(9B)-C(8B)-C(14B)
108.8(4)
108.8(4)
105.3(4)
110.4(4)
110.2(4)
112.6(4)
C(10B)-C(8B)-C(14B) 109.2(4)
N(12B)-C(15B)-C(16B) 112.2(4)
C(23B)-C(18B)-C(19B) 115.5(5)
C(23B)-C(18B)-C(17B) 122.7(5)
C(19B)-C(18B)-C(17B) 121.8(5)
C(18B)-C(17B)-C(16B) 115.1(4)
C(18B)-C(23B)-C(22B) 122.1(5)
C(21B)-C(22B)-C(23B) 119.7(6)
C(9B)-C(4B)-C(3B)
C(9B)-C(4B)-C(5B)
C(3B)-C(4B)-C(5B)
113.2(5)
119.7(5)
127.0(5)
S18

S19

2
3
Table S9. Anisotropic displacement parameters (Å x 10 ) for 09061_0m. The anisotropic
2 11 12
2
2
displacement factor exponent takes the form: -2π [ h a* U + ... + 2 h k a* b* U
______________________________________________________________________________
11 22 33 23 13 12
]
U
U
U
U
U
U
______________________________________________________________________________
S(1A) 45(1)
S(1B) 52(1)
34(1)
35(1)
44(2)
38(2)
33(2)
36(2)
43(2)
53(2)
30(2)
35(2)
37(2)
38(3)
40(2)
41(2)
36(2)
34(3)
40(3)
36(3)
45(3)
35(3)
36(3)
37(3)
46(3)
37(3)
46(3)
36(3)
51(4)
40(3)
31(3)
40(3)
35(3)
42(3)
43(3)
42(3)
44(1)
47(1)
52(2)
36(2)
65(2)
70(2)
50(2)
59(2)
42(2)
38(2)
39(2)
47(3)
38(2)
61(2)
42(2)
62(4)
40(3)
46(3)
38(3)
48(3)
48(3)
45(3)
49(3)
43(3)
42(3)
50(3)
36(3)
49(3)
39(3)
42(3)
44(3)
40(3)
46(3)
44(3)
1(1)
1(1)
2(2)
2(2)
-4(2)
-9(2)
-3(2)
-7(2)
3(2)
-2(2)
-8(2)
-5(2)
2(2)
-8(2)
1(2)
-1(3)
-8(2)
-1(3)
1(2)
2(3)
1(3)
-2(2)
4(3)
-5(2)
-8(3)
0(2)
6(3)
-3(2)
2(2)
3(2)
1(2)
0(2)
0(3)
1(2)
3(1)
-4(1)
0(1)
1(2)
2(2)
-9(2)
1(1)
9(2)
0(2)
0(2)
5(2)
-4(2)
4(2)
0(1)
-1(2)
-2(3)
-1(2)
7(2)
6(2)
13(2)
-4(2)
-4(2)
5(2)
3(2)
2(2)
-2(2)
0(2)
2(2)
5(2)
12(2)
2(2)
1(2)
-2(2)
1(2)
-1(1)
-1(1)
-10(1)
-5(2)
4(1)
F(19B) 52(2)
O(7B) 44(2)
F(2A) 61(2)
F(2B)
80(2)
7(2)
O(24B) 30(2)
F(19A) 64(2)
N(25A) 28(2)
N(12A) 32(2)
N(12B) 31(2)
C(13A) 28(2)
O(7A) 46(2)
O(24A) 29(2)
N(25B) 24(2)
C(2B) 45(3)
C(24B) 26(2)
C(19B) 36(3)
C(5A) 51(3)
C(23A) 46(3)
C(2A) 31(2)
C(15A) 29(2)
C(27B) 45(3)
C(17A) 43(3)
C(3A) 34(2)
C(16B) 31(2)
C(6B) 46(3)
C(11B) 29(2)
C(8A) 35(2)
C(18A) 41(3)
C(10B) 36(2)
C(10A) 31(2)
C(4A) 27(2)
C(13B) 29(2)
-1(1)
9(2)
5(2)
1(2)
-2(2)
1(2)
-4(2)
2(2)
-2(2)
1(2)
-6(2)
-1(2)
-4(2)
7(2)
-1(2)
1(2)
0(2)
-2(2)
-2(2)
-4(2)
-4(2)
-3(2)
1(2)
-3(2)
-2(2)
2(2)
-1(2)
2(2)
S20

C(21B) 43(3)
C(11A) 34(2)
C(22A) 54(3)
C(20A) 43(3)
C(9A) 27(2)
C(19A) 46(3)
C(14A) 33(2)
C(28A) 38(3)
C(21A) 50(3)
C(24A) 41(3)
C(9B) 28(2)
C(26A) 31(2)
C(6A) 47(3)
C(26B) 30(2)
C(16A) 34(2)
C(3B) 44(3)
C(14B) 30(2)
C(20B) 41(3)
C(5B) 41(3)
C(8B) 33(2)
C(15B) 31(2)
C(27A) 66(4)
C(18B) 36(2)
C(17B) 36(2)
C(23B) 44(3)
C(22B) 55(3)
C(28B) 44(3)
C(4B) 30(2)
49(3)
37(3)
37(3)
48(3)
35(3)
36(3)
39(3)
37(3)
48(3)
38(3)
43(3)
39(3)
42(3)
45(3)
39(3)
44(3)
42(3)
44(3)
62(4)
32(3)
43(3)
52(4)
40(3)
42(3)
43(3)
51(4)
75(4)
46(3)
45(3)
40(3)
41(3)
40(3)
42(3)
41(3)
43(3)
93(5)
39(3)
27(3)
35(3)
46(3)
36(3)
39(3)
41(3)
48(3)
39(3)
54(3)
32(3)
40(3)
48(3)
56(4)
45(3)
43(3)
51(3)
47(3)
46(3)
38(3)
-5(3)
-4(2)
-4(2)
7(3)
-6(2)
-4(2)
7(2)
3(2)
-1(2)
11(2)
-4(2)
2(3)
0(2)
4(2)
1(2)
-2(2)
-2(2)
3(2)
2(2)
-3(2)
-1(2)
0(2)
3(2)
1(2)
3(2)
-11(3)
5(2)
1(2)
7(2)
8(3)
3(2)
3(2)
2(3)
-1(2)
-3(3)
6(2)
2(2)
-1(2)
3(2)
1(2)
-1(2)
11(3)
7(3)
0(2)
-1(2)
-5(3)
-1(2)
-4(2)
2(2)
-3(2)
2(2)
1(2)
5(2)
-4(2)
4(2)
6(2)
2(2)
-2(2)
-3(2)
-4(2)
-5(2)
-1(3)
0(2)
-13(3)
-2(3)
-6(3)
-3(3)
1(2)
0(3)
-2(2)
8(3)
-6(3)
-6(3)
-1(2)
-11(3)
0(3)
5(2)
-2(2)
-10(2)
2(3)
18(3)
-4(3)
15(3)
-2(2)
______________________________________________________________________________
S21

4
2
3
Table S10. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 )
for 09061_0m.
________________________________________________________________________________
x
y
z
U(eq)
________________________________________________________________________________
H(25A)
H(13A)
H(13B)
H(25B)
H(5A1)
H(5A2)
H(23A)
H(15A)
H(15B)
H(27A)
H(27B)
H(27C)
H(17A)
H(17B)
H(3A)
3406
7188
6088
1621
4400
3038
5451
5220
6555
-172
510
2131
4174
3920
6925
5522
5244
2784
3063
3292
5752
5149
5656
4054
3442
6815
7919
6924
6426
7428
7652
6293
6647
4897
5168
7494
7180
8689
3827
4037
2686
4174
5255
5047
671
3404
4225
9400
7433
6736
-1756
2845
2285
8333
9086
8443
368
40
46
46
41
53
53
51
45
45
70
70
70
49
49
48
47
53
53
47
47
46
46
45
45
46
46
55
45
45
52
53
47
47
1438
5433
6323
3843
924
-31
6687
8768
2567
3358
6961
5838
6531
5451
3382
2579
5702
6740
13572
3446
2138
-3403
-2233
3339
4642
H(16B)
H(6B1)
H(6B2)
H(11A)
H(11B)
H(10A)
H(10B)
H(10C)
H(10D)
H(13C)
H(13D)
H(21B)
H(11C)
H(11D)
H(22A)
H(20A)
H(14A)
H(14B)
-1693
-2469
1161
214
750
1328
2672
3774
-2141
-2881
2738
3689
3267
3929
1665
6211
6671
S22

H(28A)
H(28B)
H(28C)
H(21A)
H(26A)
H(6A1)
H(6A2)
H(26B)
H(16A)
H(3B)
3494
3593
2504
2025
5370
5739
4671
-92
930
370
1833
864
85
85
85
55
47
50
50
46
46
55
45
45
56
54
54
49
49
88
88
88
49
49
55
61
83
83
83
962
671
3377
1140
4881
4388
6003
3191
4561
6381
6123
9446
5769
6136
7944
8283
1276
680
-3637
795
6302
6816
10288
1051
2803
5265
6416
12064
2057
2391
7961
7339
-1180
-985
3906
-200
-2789
-1942
2883
-1411
13
H(14C)
H(14D)
H(20B)
H(5B1)
H(5B2)
H(15C)
H(15D)
H(27D)
H(27E)
H(27F)
H(17C)
H(17D)
H(23B)
H(22B)
H(28D)
H(28E)
H(28F)
-1918
-719
3459
4539
5044
-400
-1364
-216
1210
2787
1859
1990
1432
8856
8355
7694
7800
5923
5418
6185
-1163
9290
9900
11659
13353
10345
10989
11386
________________________________________________________________________________
S23

Table S11. Torsion angles [°] for 09061_0m.
________________________________________________________________
C(15A)-N(12A)-C(13A)-C(14A)
C(11A)-N(12A)-C(13A)-C(14A)
C(9B)-S(1B)-C(2B)-C(3B)
-179.5(4)
-58.4(5)
-0.3(4)
C(9B)-S(1B)-C(2B)-F(2B)
179.8(4)
10.0(7)
C(26B)-N(25B)-C(24B)-O(24B)
C(26B)-N(25B)-C(24B)-C(16B)
C(9A)-S(1A)-C(2A)-C(3A)
-170.6(5)
0.0(4)
C(9A)-S(1A)-C(2A)-F(2A)
-179.3(4)
-166.9(4)
72.7(5)
C(13A)-N(12A)-C(15A)-C(16A)
C(11A)-N(12A)-C(15A)-C(16A)
F(2A)-C(2A)-C(3A)-C(4A)
178.5(4)
-0.8(5)
S(1A)-C(2A)-C(3A)-C(4A)
O(24B)-C(24B)-C(16B)-C(17B)
N(25B)-C(24B)-C(16B)-C(17B)
O(24B)-C(24B)-C(16B)-C(15B)
N(25B)-C(24B)-C(16B)-C(15B)
C(8B)-O(7B)-C(6B)-C(5B)
53.8(6)
-125.5(5)
-66.5(6)
114.1(5)
-67.5(5)
170.8(4)
-63.1(5)
-43.2(5)
-165.5(4)
80.9(5)
C(15B)-N(12B)-C(11B)-C(10B)
C(13B)-N(12B)-C(11B)-C(10B)
C(6A)-O(7A)-C(8A)-C(9A)
C(6A)-O(7A)-C(8A)-C(10A)
C(6A)-O(7A)-C(8A)-C(14A)
C(22A)-C(23A)-C(18A)-C(19A)
C(22A)-C(23A)-C(18A)-C(17A)
C(16A)-C(17A)-C(18A)-C(23A)
C(16A)-C(17A)-C(18A)-C(19A)
N(12B)-C(11B)-C(10B)-C(8B)
O(7A)-C(8A)-C(10A)-C(11A)
C(9A)-C(8A)-C(10A)-C(11A)
C(14A)-C(8A)-C(10A)-C(11A)
C(2A)-C(3A)-C(4A)-C(9A)
C(2A)-C(3A)-C(4A)-C(5A)
C(6A)-C(5A)-C(4A)-C(9A)
C(6A)-C(5A)-C(4A)-C(3A)
C(15B)-N(12B)-C(13B)-C(14B)
C(11B)-N(12B)-C(13B)-C(14B)
C(15A)-N(12A)-C(11A)-C(10A)
-1.1(7)
176.9(5)
-91.6(6)
86.3(6)
57.1(6)
-59.7(5)
-178.3(4)
56.5(5)
1.4(6)
-179.4(4)
24.2(6)
-154.9(4)
-170.1(4)
64.6(5)
177.0(4)
S24

C(13A)-N(12A)-C(11A)-C(10A)
C(8A)-C(10A)-C(11A)-N(12A)
C(18A)-C(23A)-C(22A)-C(21A)
C(3A)-C(4A)-C(9A)-C(8A)
C(5A)-C(4A)-C(9A)-C(8A)
C(3A)-C(4A)-C(9A)-S(1A)
57.4(5)
-58.9(6)
0.4(8)
176.0(4)
-3.2(7)
-1.4(5)
C(5A)-C(4A)-C(9A)-S(1A)
179.4(3)
11.0(6)
127.5(5)
-111.1(5)
-171.9(3)
-55.4(5)
66.0(5)
0.8(4)
O(7A)-C(8A)-C(9A)-C(4A)
C(10A)-C(8A)-C(9A)-C(4A)
C(14A)-C(8A)-C(9A)-C(4A)
O(7A)-C(8A)-C(9A)-S(1A)
C(10A)-C(8A)-C(9A)-S(1A)
C(14A)-C(8A)-C(9A)-S(1A)
C(2A)-S(1A)-C(9A)-C(4A)
C(2A)-S(1A)-C(9A)-C(8A)
-176.7(4)
-179.7(5)
-0.2(8)
C(21A)-C(20A)-C(19A)-F(19A)
C(21A)-C(20A)-C(19A)-C(18A)
C(23A)-C(18A)-C(19A)-F(19A)
C(17A)-C(18A)-C(19A)-F(19A)
C(23A)-C(18A)-C(19A)-C(20A)
C(17A)-C(18A)-C(19A)-C(20A)
N(12A)-C(13A)-C(14A)-C(8A)
O(7A)-C(8A)-C(14A)-C(13A)
C(9A)-C(8A)-C(14A)-C(13A)
C(10A)-C(8A)-C(14A)-C(13A)
C(19A)-C(20A)-C(21A)-C(22A)
C(23A)-C(22A)-C(21A)-C(20A)
C(26A)-N(25A)-C(24A)-O(24A)
C(26A)-N(25A)-C(24A)-C(16A)
C(2B)-S(1B)-C(9B)-C(4B)
-179.4(4)
2.5(7)
1.1(7)
-177.0(5)
59.8(6)
56.0(5)
177.4(4)
-56.8(5)
-0.6(8)
0.5(8)
-3.7(7)
176.6(4)
0.4(4)
C(2B)-S(1B)-C(9B)-C(8B)
-177.6(4)
141.2(5)
-95.7(5)
69.4(5)
-55.0(5)
97.6(5)
-137.3(5)
77.5(5)
-162.5(4)
C(24A)-N(25A)-C(26A)-C(28A)
C(24A)-N(25A)-C(26A)-C(27A)
C(8A)-O(7A)-C(6A)-C(5A)
C(4A)-C(5A)-C(6A)-O(7A)
C(24B)-N(25B)-C(26B)-C(27B)
C(24B)-N(25B)-C(26B)-C(28B)
C(18A)-C(17A)-C(16A)-C(24A)
C(18A)-C(17A)-C(16A)-C(15A)
S25

O(24A)-C(24A)-C(16A)-C(17A)
N(25A)-C(24A)-C(16A)-C(17A)
O(24A)-C(24A)-C(16A)-C(15A)
N(25A)-C(24A)-C(16A)-C(15A)
N(12A)-C(15A)-C(16A)-C(17A)
N(12A)-C(15A)-C(16A)-C(24A)
F(2B)-C(2B)-C(3B)-C(4B)
66.2(6)
-114.0(5)
-56.5(6)
123.3(4)
58.6(6)
-178.9(4)
-180.0(5)
0.1(6)
S(1B)-C(2B)-C(3B)-C(4B)
N(12B)-C(13B)-C(14B)-C(8B)
F(19B)-C(19B)-C(20B)-C(21B)
C(18B)-C(19B)-C(20B)-C(21B)
C(22B)-C(21B)-C(20B)-C(19B)
O(7B)-C(6B)-C(5B)-C(4B)
-58.7(5)
-179.1(5)
2.6(8)
-0.4(8)
53.0(5)
C(6B)-O(7B)-C(8B)-C(9B)
40.4(5)
C(6B)-O(7B)-C(8B)-C(10B)
C(6B)-O(7B)-C(8B)-C(14B)
C(4B)-C(9B)-C(8B)-O(7B)
158.8(4)
-83.5(5)
-5.1(6)
S(1B)-C(9B)-C(8B)-O(7B)
172.5(3)
-120.2(5)
57.4(5)
C(4B)-C(9B)-C(8B)-C(10B)
S(1B)-C(9B)-C(8B)-C(10B)
C(4B)-C(9B)-C(8B)-C(14B)
S(1B)-C(9B)-C(8B)-C(14B)
C(11B)-C(10B)-C(8B)-O(7B)
C(11B)-C(10B)-C(8B)-C(9B)
C(11B)-C(10B)-C(8B)-C(14B)
C(13B)-C(14B)-C(8B)-O(7B)
C(13B)-C(14B)-C(8B)-C(9B)
C(13B)-C(14B)-C(8B)-C(10B)
C(13B)-N(12B)-C(15B)-C(16B)
C(11B)-N(12B)-C(15B)-C(16B)
C(24B)-C(16B)-C(15B)-N(12B)
C(17B)-C(16B)-C(15B)-N(12B)
C(20B)-C(19B)-C(18B)-C(23B)
F(19B)-C(19B)-C(18B)-C(23B)
C(20B)-C(19B)-C(18B)-C(17B)
F(19B)-C(19B)-C(18B)-C(17B)
C(23B)-C(18B)-C(17B)-C(16B)
C(19B)-C(18B)-C(17B)-C(16B)
C(24B)-C(16B)-C(17B)-C(18B)
117.4(5)
-65.0(5)
68.5(5)
-174.2(4)
-49.9(6)
-65.0(5)
173.3(4)
50.2(5)
154.9(4)
-81.5(5)
-46.1(5)
-167.8(4)
-2.9(7)
178.9(4)
178.7(5)
0.4(7)
-74.3(6)
104.0(6)
65.6(6)
S26

C(15B)-C(16B)-C(17B)-C(18B)
C(19B)-C(18B)-C(23B)-C(22B)
C(17B)-C(18B)-C(23B)-C(22B)
C(20B)-C(21B)-C(22B)-C(23B)
C(18B)-C(23B)-C(22B)-C(21B)
C(8B)-C(9B)-C(4B)-C(3B)
S(1B)-C(9B)-C(4B)-C(3B)
C(8B)-C(9B)-C(4B)-C(5B)
S(1B)-C(9B)-C(4B)-C(5B)
C(2B)-C(3B)-C(4B)-C(9B)
C(2B)-C(3B)-C(4B)-C(5B)
C(6B)-C(5B)-C(4B)-C(9B)
C(6B)-C(5B)-C(4B)-C(3B)
-175.5(4)
1.0(7)
179.4(5)
-1.4(8)
1.0(8)
177.5(4)
-0.4(5)
-4.0(7)
178.1(4)
0.2(6)
-178.2(5)
-19.9(6)
158.4(5)
________________________________________________________________
Symmetry transformations used to generate equivalent atoms.
S27

Separation of [11C](S)-10c with HPLC
Conditions: Luna C18 column (10 µm; 10 × 250 mm; Phenomenex) eluted at 8.0 mL/min for 5
min and then at 6.0 mL/min with MeCN-100 mM HCOONH4 solution (50: 50 v/v), with eluate
monitored for absorbance at 235 nm. tRs: [11C](S)-10c, 12.32 min; precursor (S)-9c, 10.93 min.
Radioactivity
0.75
0.50
0.25
0.00
0.75
0.50
0.25
0.00
0
2
4
6
8
10
12
14
Minutes
Absorbance at 235 nm
Det 166
Retention Time
1.0
1.0
0.5
0.0
-0.5
0.5
0.0
-0.5
0
2
4
6
8
10
12
14
Minutes
Radioactivity distribution
Time (min) Area Area (%)
2.163 3170566
2.462 1530971
16.41
7.92
3.096
4.358
307363
802248
1.59
4.15
12.321 13512019
69.93
S28

Analysis of [11C](S)-10a with radio-HPLC
Conditions: Luna C18 column (10 µm; 10 × 250 mm; Phenomenex) eluted at 3.0 mL/min with
MeCN-10 mM (NH4)2CO3 solution (55: 45 v/v) with eluate monitored for absorbance at 235 nm.
tRs: [11C](S)-10a, 4.98 min; (S)-10a, 5.75 min.
Radioactivity
2
1
0
2
1
0
0
1
2
3
4
5
6
7
8
Minutes
Absorbance at 235 nm
Det 166
Retention Time
0.0025
0.0000
-0.0025
0.0025
0.0000
-0.0025
0
1
2
3
4
5
6
7
8
Minutes
Radiochemical purity:
Time (min) Area
Area (%) Height
Height (%)
4.98 38639759 100.00 1773523 100.00
% Chemical purity:
Time (min) Area
4.258 1272
Area (%) Height
Height (%)
8.70
6.94
90
4.725 17050
93.06
945
91.30
S29

Analysis of [11C](S)-10b with radio-HPLC
Conditions: Luna C18 column (10 µm; 10 × 250 mm; Phenomenex) eluted at 3.0 mL/min with
MeCN-100 mM HCOONH4 solution (60: 40 v/v) with eluate monitored for absorbance at 235 nm.
tRs: [11C](S)-10b, 5.09 min; (S)-10b, 4.842 min.
Radioactivity
1.0
0.5
0.0
1.0
0.5
0.0
0
1
2
3
4
5
6
7
8
9
10
Minutes
Absorbance at 235 nm
Det 166
Retention Time
0.000
0.000
-0.005
-0.010
-0.015
-0.005
-0.010
-0.015
0
1
2
3
4
5
6
7
8
9
10
Minutes
Radiochemical purity:
Area Area (%) Height Height (%)
18601456 100 920395 100
Chemical purity:
Area (%) Height Height (%)
Time
(min)
5.09
Time
(min)
4.842
Area
27480
100
1421
100
S30