#224
FIRSTINHUMANCHARACTERIZATIONOFPI-2620,ANEXT
GENERATIONPETTRACERFORASSESSINGTAUIN
ALZHEIMER’SDISEASEANDOTHERTAUOPATHIES
OlivierBarret1,JohnSeibyl1,AndrewStephens2,JenniferMadonia1,DavidAlagille1,AndreMueller2,MathiasBerndt2,
HeikoKroth3,AndreasMuhs3,AndreaPfeifer3,GillesTamagnan1,Ludger Dinkelborg2,KennethMarek1,1Molecular
2
3
Neuroimaging,NewHaven,USA, Piramal Imaging,Berlin,Germany, ACImmune,SA,Lausanne,Switzerland
RESULTS
BACKGROUND / RATIONALE
2
Cing_Ant_L
4
MMSE17
Putamen_L
2
AD01
Cing_Ant_R
MMSE7
CaudateNucl_L
CaudateNucl_R
Putamen_R
Pallidum_L
2
AD02
Pallidum_R
0
50
100
150
0
200
Time (min)
0
50
100
150
200
0
0
50
Time (min)
100
0
200 0
150
50
Time (min)
100
S_nigra_R
150
FL_OFC_L
Time (min)
FL_OFC_R
TL_SupLat_L
3
2
2
1
0
1
0
50
100
150
200
Time (min)
0
0
50
100
Time (min)
150
200
3
3
2
0
TL_InfLat_R
PL_R
PL_L
OL_L
OL_R
1
0
50
100
0
200 0
150
TL_Mesial_L
50
100
0.0
60-90minp.i.
AD09
TL_Mesial_R
Cing_Post_L
150
Time (min)
Time (min)
MMSE26
TL_InfLat_L
2
1
AD04
TL_SupLat_R
SUVr (cerebellar cortex)
3
5.0
MMSE22
S_nigra_L
SUVr
0
4
AD
subject
09
6
MMSE26
SUV (g/mL)
4
2
6
MMSE22
SUV (g/mL)
MMSE7
4
AD
subject
04
SUV (g/mL)
6
SUVr (cerebellar cortex)
• Invivopreclinicalstudiesshowhighbrainuptakeandfastwash-outinmiceandnon-humanprimate.
6
AD
subject
02
SUVr (cerebellar cortex)
• PI-2620bindstobothTauisoforms3Rand4Randdemonstrateshighselectivityoverbeta-amyloid,
MAOAandMAOB,withverylowoff-targetbinding.
AD
subject
01
SUV (g/mL)
• ThenovelPETtautracerPI-2620hasanIC50of1.8nM fortauinADbrainhomogenatecompetitionassaysandbindsspecificallytotaudepositsonADbrainsections(Braak I-VI),Pick’sandPSP
pathology.
ADsubjects:SUVand SUVr
SUVr (cerebellar cortex)
• Positronemissiontomographymayproveausefultoolfordetectingthepresenceandspatialextent
ofbraintauaccumulation,akeypathologicfeatureofAlzheimer’sdisease(AD)andothernon-AD
tauopathies.Currenttautracerssufferfromsub-optimalkineticsandhighoff-targetbinding,
confoundingquantification,aswellasvariableaffinityfortauisoforms,diminishingutilityfor
evaluatingnon-ADtauopathies likeprogressivesupranuclear palsy(PSP).
MMSE17
Cing_Post_R
PSPsubjects:SUVand SUVr
Substantia
nigra
Pallidum
6.0
SUVr (cerebellar cortex)
200
0
PSP07
AD04
19
65
HC05
N/A
26
51
N/A
0.5
29
11
0
340.4
N/A
6
347.8
N/A
MNI-960-01-01-07
PSP07
66
26
N/A
N/A
38
351.5
MNI-960-01-01-08
HC08
53
29
0
5
N/A
355.2
MNI-960-01-01-09
AD09
80
17
0.5
14
N/A
351.5
Fig.1.Healthycontrol
biodistribution anddosimetry
276-322
12mmsmoothingapplied
HCsubjects:SUVand SUVr
HC05
HC05
6
SUVr (cerebellar cortex)
164-210
1. Eliminationisviaboth
10.0
hepatobiliary(mainroute)and
urinarypathways.
2. Targetorganswithhighest
exposurearegallbladderwall
andupperlargeintestine.
3. TheEffectiveDoseper185
MBq(5mCi)injectionis4.1mSv
withnoUBvoiding,and4.0mSv
0.0
with2hourUBvoidinginterval
foradultmale,whichcompares
favorablytoother18F
radiopharmaceuticals.
3
SUV (g/mL)
51yrs,MMSE29
4
2
2
1
0
HC08
0
50
100
150
0
200
Time (min)
SUVr
0.0
60-90minp.i.
150
200
2
2
0
100
3
53yrs,MMSE29
4
50
SUVr (cerebellar cortex)
SUV (g/mL)
5.0
0
Time (min)
HC08
6
1
0
HC
05
FL_OFC_L
1.21
FL_OFC_R
1.19
TL_SupLat_L
1.07
TL_SupLat_R
1.17
TL_InfLat_L
1.06
TL_InfLat_R
1.12
TL_Mesial_L
1.07
TL_Mesial_R
1.20
PL_L
1.07
PL_R
1.11
OL_L
1.17
OL_R
1.22
Cing_Ant_L
0.96
Cing_Ant_R
1.00
Cing_Post_L
0.99
Cing_Post_R
0.95
CaudateNucl_L
0.85
CaudateNucl_R
0.88
Putamen_L
0.93
Putamen_R
1.07
Pallidum_L
1.09
Pallidum_R
1.07
S_nigra_L
1.68
S_nigra_R
1.54
HC
PSP
PSP
AD
AD
AD
AD
08
03
07
01
04
02
09
1.50
1.30
1.27 1.32 1.60
1.03
1.40
1.49
1.30
1.30 1.37 1.31
1.05
1.33
1.36
1.03
1.15 1.30 2.01
1.06
2.00
1.81
1.01
1.17 1.27 1.61
1.08
1.46
1.77
1.09
1.27 1.23 2.27
1.15
2.27
2.10
1.07
1.17 1.19 1.70
1.15
1.57
1.71
1.04
1.27 1.25 1.70
1.15
1.85
2.16
1.15
1.22 1.34 1.40
1.27
1.23
1.06
1.03
1.04 1.25 1.69
0.95
1.53
1.13
0.98
1.04 1.20 1.55
0.94
1.21
1.23
1.12
1.19 1.38 2.04
1.04
1.36
1.50
1.11
1.22 1.41 1.65
1.10
1.29
0.89
0.88
0.97 1.08 1.05
0.75
1.17
0.90
0.84
0.85 1.05 0.91
0.88
1.04
1.07
0.88
1.05 1.15 1.64
0.86
1.39
1.14
0.86
0.99 1.17 1.63
0.86
1.26
0.67
0.64
0.89 0.96 0.88
0.66
0.85
0.64
0.67
0.85 1.05 0.93
0.54
0.97
1.01
0.84
1.42 1.19 1.11
0.88
1.32
1.03
0.73
1.26 1.37 0.92
0.87
1.12
0.96
0.83
2.11 1.59 1.12
0.97
1.19
1.00
0.74
1.99 1.85 0.94
0.84
1.26
1.54
1.15
2.58 2.03 1.16
1.21
1.57
1.08
1.05
2.41 1.70 1.04
1.39
1.60
50
100
Time (min)
150
200
0
0
50
100
150
100
150
200
Time (min)
Left Cortical VOIs
3
200
Time (min)
Fig.2aPETintwohealthycontrolsacquired60-90minpostinjectionof350MBq of
18F-PI-2620.Notelackofnon-specific,off-targetuptake.SUVtime-activitycurves
showhighbrainpenetranceandfastwash-outwithsecularequilibriumachievedat
50minandpersistingforthenext1.5hinAD,PSP,andcontrols(Fig.2b,c).
Left Subcortical VOIs
HC Subject 5
HC Subject 8
2
PSP Subject 3
PSP Subject 7
AD Subject 1
1
AD Subject 4
AD Subject 2
0
3
2
1
0
AD Subject 9
Fig.3PETSUVr forleftcorticalandsubcorticalbrainregions
showgoodseparationbetweenvisuallydetectedareasof
higheruptakedescribedabove(Fig2)andelevatedSUVrs.
SUVR-1andBPND CorrelationinADSubjects
Percent Unchanged Parent
SUV(g/ml)
min
50
Table2.SUVr Measures
358.9
54
0
Time (min)
ni
gr
a
75
Cing_Post_R
S_nigra_R
S_nigra_L
Pallidum_R
Pallidum_L
Cerebellum
Putamen_R
Putamen_L
CaudateNucl_R
CaudateNucl_L
S_
PSP03
0
200
lli
du
m
351.5
OL_L
Pa
N/A
150
en
21
100
m
0.5
PL_R
Cing_Post_L
Pu
ta
22
PL_L
200
Cing_Ant_R
uc
l
70
150
Cing_Ant_L
eN
AD02
50
SUVr (cerebellar cortex)
MNI-960-01-01-02
100
OL_R
au
da
t
340.4
50
C
N/A
0
Fig.4CorrelationofSUVrs andBPnd
determinedbynon-invasivePKmodeling
suggests60-90minsmaybestalignwith
BPnd.
Fig.5MetabolismofPI2620shows,similarly
acrosssubjects,rapid
kineticswith20%of
parentpresentat
60minute(top)and
productionofhydrophilic
metabolites(bottom).The
latterareunlikelytocross
theblood-brainbarrier.
100
% Parent fraction
53
0
1
HC Subject 5
80
HC Subject 8
PSP Subject 3
60
PSP Subject 7
40
AD Subject 1
20
AD Subject 4
AD Subject 2
0
0
20
40
60
80
AD Subject 9
Time (min)
Total Plasma
1.5
HC Subject 5
HC Subject 8
SUV (g/mL)
2
TL_Mesial_R
2
A
n
in
g_ t
Po
st
7
TL_Mesial_L
3
C
63
TL_InfLat_R
Time (min)
g_
AD01
66-87
0
60-90min
O
L
MNI-960-01-01-01
22-43
150
2
in
Injected
dose(MBq)
L
0-10
100
4
C
PSPScale
Subject03-01-02(male)
R
50
6
PL
ADAS-Cog
MNI-960-01-01-05
0
Time (min)
SUVr
CDR
TL_InfLat_L
2
0
SUVr (cerebellar cortex)
MMSE
TL_SupLat_R
1
FL
_
TL OF
_S C
up
TL La
_I t
n
TL fLa
_M t
es
ia
l
Age
TL_SupLat_L
3
2
75yrs,MMSE19,PSPscale 54
Cohort
MNI-960-01-01-04
PSP03
0.0
Subject number
MNI-960-01-01-03
FL_OFC_R
4
RESULTS
Table1.BaselineCharacteristics
FL_OFC_L
6
SUVr (cerebellar cortex)
• Inanongoingclinicalstudy,participantsdiagnosedwithmildAlzheimer’s(AD),non-AD
tauopathies,andhealthycontrols(HC)underwentdynamicPETimagingforapproximately3h
following350MBq bolusinjectionof18F-PI-2620.ADsubjectsandcontrolshadscreening
florbetaben PETscreeningscanstoconfirmcohort- appropriateamyloidstatus
• Venousbloodwasobtainedtocharacterizethemetabolismofparentcompound.
• SUVandSUVrs werecalculatedforbrainregionsderivedfromtheHammerstemplateplacedon
eachspatiallynormalized,greymattersegmentedPETimagevolume.
• Inaddition,asinglehumanbiodistribution/dosimetrystudywasperformedinamalecontrolwith
preliminaryestimatesoftargetorganradiationabsorbeddoseandEffectiveDose(ED).
SUV (g/mL)
STUDY DESIGN
Fig.2b,c PETinfourAD(above)andtwoPSP(below)participantsacquired60-90minpostinjectionof350
MBq of18F-PI-2620.ThreeoftheADpatientsshowtypicalasymmetricpatternsoftraceruptakeinvolving
temporallobes,precuneus,andpostcingulate.ThethirdADsubject,verymildclinically,showsnouptake,a
phenomenanotedwithAV1451(Pontecorvo,etal,Brain,Jan11,2017).ThePSPsubjects(below)showfocally
discreteuptakeinsubstantia nigra andpallidum,consistentwithpathologicalreportsintheliterature.
SUV (g/mL)
Objective:ToextendthesestudiestofirstinhumanevaluationofthetauPETtracerPI-2620(MNI-960)
inresearchparticipantswithandwithoutsuspectedtaupathology.
Cerebellum
1.0
PSP Subject 3
PSP Subject 7
AD Subject 1
0.5
AD Subject 4
AD Subject 2
0.0
0
20
40
60
80
AD Subject 9
Time (min)
CONCLUSIONS
• InitialclinicaldatainADsubjectsshowsrobustbrainuptakeandfastwash-outinnontargetregions.
• Noincreaseduptakewasnotedinchoroidplexus,striatum,amygdala,orotherregions
seeninfirstgenerationtauagents.
• SUVr timecurvessuggestaplateauoccurs60-90minpostinjectionwithresultantSUVrs
inabnormalregionsupto2.5-2.8.
• Blooddataconfirmedfastkineticswith20%ofparentcompoundpresentat60min.
• Nolipophilicmetaboliteswereobserved.
• ADandPSPsubjectsshowexpectedpatternsoftauuptake.
• Non-invasivepk modelingindicatesSUVr (60-90min)couldbeagoodproxyforBPnd
pendingfullvalidationofquantitativeoutcomemeasuresusingmetabolitecorrected
arterialinputfunctions.