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Small molecule PSMA inhibitors for targeted molecular imaging of prostate cancer
Small molecule PSMA inhibitors for targeted molecular imaging of prostate cancer
John W. Babich, Ph.D.Whistler, 2008
The attraction of radioiodinesThe attraction of radioiodines
Decay modes and half lives availableGamma, beta, auger12h, 8d, 60d, I-123 has the highest practical specific activity and is ideal for SPECTI-131 is the most thoroughly studied and successful from a therapy perspectiveI-125 is excellent for ARG and in vitro and in vivo experimentation
Ease of substituting one iodine radionuclide for anotherImaging - to - therapy - to - imagingDetection - to - treatment -to - monitoring therapeutic response
Natural” fit from a medicinal chemistry approach Ease of incorporation into organic molecules – single covalent bond with carbonSimilar electro-negativity to carbonSimilar volume to methyl or ethyl group
Can be readily synthesized on a macroscaleEnables absolute structural elucidationEnables scale up for toxicological and pharmacological evaluation
Prostate Cancer and PSMAProstate Cancer and PSMA
Prostate cancer is the second leading cause of cancer-related deaths amongst men in the USA; ~200,000 men are diagnosed with prostate cancer each year, and ~30,000 will die from the diseaseChallenging to detect recurrent disease despite the availability of multiple imaging modalities including MRI, CT, bone scan, and several PET agentsPSMA is a membrane-bound protein expressed in normal prostate, and expression is increased in prostate cancer and numerous reports demonstrate a correlation of PSMA expression with PSA level, tumor stage, disease recurrence, and time to progressionRadiolabeled PSMA antibodies have met with limited success due primarily to the long plasma half-life and reduced tissue penetrability, and most likely the intracellular epitope in the case of ProstascintMIP is developing small molecules that bind to the catalytic domain of PSMA
PSMA: Structure and FunctionPSMA: Structure and Function
110 kDa, type II, highly glycosylatedtransmembrane proteinMember of a family of zinc-dependent exopeptidases with glutamate carboxypeptidase activity
NAALADase, FOLHI
Found in prostate, brain, kidney proximal tubules, intestinal brush border membranes, and tumor neovasculatureRole of PSMA in the prostate is unknown Filamin A Binding
Catalytic
Dimerization
Glycine-rich
Proline-rich
Transmembrane
N
C
UnknownFunction
Extracellular
Intracellular
Davis et al. (2005) Proc. Natl. Acad. Sci. USA 102, 5981-5986
Targeting the Active Site of PSMATargeting the Active Site of PSMA
Substrate binding domain contains
two basic subpockets.
The major basic patch binds
glutamate via electrostatic
interactions
Catalytic domain contains a
binuclear zinc binding site
coordinating a water molecule where
hydrolysis of peptide bond occurs
NAAG Binding to PSMA
Design of Glutamate Urea HeterodimersDesign of Glutamate Urea Heterodimers
S1 and S1’ permit structural modification to increase steric bulkS1’ is tolerant to relatively large hydrophobic groupsS2 and S2’ are intolerant to structural changesIt appears necessary to keep one glutamic acid unit intact
NH
COOH
COOH
NH
HOOC
COOH
O
H H
Kozikowski et al. J Med Chem. 2001 Feb 1;44(3):298-301.
S1 S1’
S2’S2 O
OHNH
O
NH
OHO
O
HO
HN RX
Glu-urea-Lys serves as an excellent building block for preparing potent PSMA inhibitors
NH2O
O
OO
NHO
O
OO
N
O
N
MeOTf, DCE
OTfNHO
O
OO
N
O
N
1)
2) hydrogenolysis
NH
NH
CO2t-Bu
O
O
O
OONH2
2 2B
4
H2N CO2t-Bu
NHCBZ
NO
O
OO
CO
DCM, CDI, TEA
triphosgene, TEA H2N CO2t-Bu
NHCBZ1)
2) hydrogenolysis
Route A
Route B
1
3
DCM = dichloromethaneCDI = carbonyldiimidazoleTEA = triethylamineMeOTf = methyl triflateCBZ = carboxybenzyloxy
Competitive Binding of Halogen-Containing Glutamate Urea Heterodimers to PSMA on LNCaP CellsCompetitive Binding of Halogen-Containing Glutamate Urea Heterodimers to PSMA on LNCaP Cells
0 0.001 0.01 0.1 1 100
30
60
90
120
Concentration (μM)
% o
f Con
trol
0 0.001 0.01 0.1 1 100
30
60
90
120
Concentration (μM)
% o
f Con
trol
NH
O
NH
O
OH
OHO
O
OH
HN
X
IC50 (nM)X2247
425 2
245 277 43
1200 2960
p-Io-I m-I p-Clo-Clm-Clp-Br p-F H
MIP-1072MIP-1035MIP-1089MIP-1107MIP-1137MIP-1131MIP-1094MIP-1090MIP-1106
-4 -3 -2 -1 0 10
30
60
90
120
MIP-1097MIP-1111
MIP-1129MIP-1110
MIP-1101MIP-1027
MIP-1095
Log Concentration (uM)
% o
f Con
trol
Competitive Binding of Halogen-Containing Glutamate Urea Heterodimers to PSMA on LNCaP CellsCompetitive Binding of Halogen-Containing Glutamate Urea Heterodimers to PSMA on LNCaP Cells
IC50 (nM)X102 412 10 20 3
p-Ip-Brp-ClHp-I p-I p-I
MIP-1095MIP-1129MIP-1110MIP-1111MIP-1097MIP-1101MIP-1027
NH
O
NH
O
OH
OHO
O
OH
HNR
X
(CO)NH(CO)NH(CO)NH(CO)NHSO2(CO)NHCH2CO
R
0 0.001 0.01 0.1 1 100
30
60
90
120
Concentration (μM)
% o
f Con
trol
0 0.001 0.01 0.1 1 100
30
60
90
120
% o
f Con
trol
Inhibition of the NAALADase Activity of PSMA by MIP-1072 and MIP-1095 Inhibition of the NAALADase Activity of PSMA by MIP-1072 and MIP-1095
NAALADase Inhibition (Ki)MIP-1072 6 nMMIP-1095 0.3 nM
NH
HN CO2H
CO2HO
CO2HO
NH
CO2H
H2N CO2H
CO2H
CO2HO
+
NAAGGlutamate
N-Acetylaspartate
Radiolabeling of MIP-1072Radiolabeling of MIP-1072
5 10 15 20 25 30 35
Minutes
2.5
5.0
7.5
10.0
mVolts
1.72
5 2.88
4
19.1
71
21.2
6721
.623
21.8
23
Channel: 1 = UV Results
0
100
200
300
400
500
600
mVolts
3.32
1
19.4
68Channel: 2 = Radio Results
WI:32WI:16
WI:8
WI:32
MIP-1072 Reference Standard
[123I]-MIP-1072
5 10 15 20 25 30Time (min)
10.07.55.02.5
600500400300200100
0
mV
olts
mV
olts
Radio
UV
RCY = 60-70%, Specific Activity >2000 mCi/μmole
O
OHNH
O
NH
OHO
O
HO
HN
123I
123I-MIP-1072O
ONH
O
NH
OO
O
O
HN
SnMe3 1) Na123I/Peracetic acid
2) TFA
5 10 15 20 25 30 35Minutes
0
50
100
150
200
0
200
400
600
mVo
lts
Radiolabeling of PSMA Inhibitor 123I-MIP-1095Radiolabeling of PSMA Inhibitor 123I-MIP-1095
RCY = 60%; RCP = 94%S.A. > 4000 mCi / µmol
UV-vis
Radio traceTime (RT) (40°C)
0 94.4 % 94.4 %
24 h 93.9 % 93.6 %
48 h 93.4 % 92.7 %
Radio-chemical Stability(pH 5 Gentisate/Ascorbate solution)
O
ONH
O
NH
OO
O
O
HN N
123I
O
OHNH
O
NH
OHO
O
HO
HN N
123I
O
ONH
O
NH
OO
O
O
HN N
SnMe3O OO
mVo
lts
123I-MIP-1095
General Synthetic Process for [123I]MIP-1095
O
ONH
O
NH
OO
O
O
HN NH
O SnMe3
Sn-MIP-1095 Precursor
1. [123I] NaI, oxidant
2. TFA/CH2Cl2
3. C18 Sep-Pak O
OHNH
O
NH
OHO
O
HO
HN NH
O123I
[123I]MIP-1095
This initial synthetic sequence resulted in a low RCY and reduced PSMA binding in vitro
Key Reaction Parameters Investigated
Iododestannylation reactionpHOrder of AdditionOxidantSolvents/solubilityReaction time
Deprotection of the intermediate t-butyl esterReaction timeSolvents
Purification of the desired final product, [123I]MIP-1095
Iododestannylation: Effect of pH
Peracetic acid oxidant and pH 2 afforded the highest RCY
O
ONH
O
NH
OO
O
O
HN NH
O SnMe3
Sn-MIP-1095 Precursor
[123I]NaIperacetic acid
sulfuric acidpH = 2 O
ONH
O
NH
OO
O
O
HN NH
O123I
[123I]MIP-1095-tri-t -butyl ester
Reaction pH RCY2 80%4 47%
5.5 30%
Iododestannylation: Order of Addition
Due to the lipophilicity of Sn-MIP-1095, organic solvents were introduced
Sn-MIP-1095 was added last due to its instability under acidic conditions
Performing the reaction directly in the 5 mL vial in which the [123I]NaI arrives allows for a faster, easier and safer manufacturing process
1. SWFI2. Acid
3. Oxidant4. AcCN
5. Sn-MIP-1095
[123I]NaI
Iododestannylation: Effect of Reaction Time & pH
O
ONH
O
NH
OO
O
O
HN NH
O SnMe3
Sn-MIP-1095 Precursor
[123I]NaIperacetic acid
sulfuric acidpH = 2 O
ONH
O
NH
OO
O
O
HN NH
O123I
[123I]MIP-1095-tri-t-butyl ester
Prolonged reaction time (> 10 min) led to deprotection of one or more of the t-butyl ester protecting groups of [123I]MIP-1095-tri-t-butyl ester leading to low RCY
Iododestannylation: Effect of Reaction Time & pH
Minutes
13.7
Exposure to radioiodination conditions for 10 minutes
5 10 15 20 25
mV
olts
0
50
13.7
0
20
80
0
100
40
30
40
0
0
20
Reference standard
Exposure to radioiodination conditions for 15 minutes
O
ONH
O
NH
OO
O
O
HN NH
O I
MIP-1095 tri-t-butyl ester
UV-Vis Chromatogram
Iododestannylation: Effect of Solvent
Sn-MIP-1095 precursor was soluble in organic solvents (i.e. AcCN, MeOH)
Deprotection of the t-butyl groups in the presence of trace amounts of methanol resulted in the formation of methyl esters
Use of t-butanol resulted in t-butyl formation during re-esterification, however, RCY less than 40% were obtained
O
ONH
O
NH
OO
O
O
HN NH
O SnMe3
Sn-MIP-1095 Precursor
[123I]NaIperacetic acid
sulfuric acidpH = 2 O
ONH
O
NH
OO
O
O
HN NH
O123I
[123I]MIP-1095-tri-t -butyl ester
t-Butyl Ester Deprotection: Effect of Solvent
The presence of trace amounts of methanol resulted in the formation of a mixture of methyl ester side products during t-butyl deprotection step
OON
H
ONH
OO
OO
HN NH
O123I
TFA/CH2Cl2
trace methanol
OOHN
H
ONH
OMeO
OHO
HN NH
O123I
OOHN
H
ONH
OMeO
OMeO
HN NH
O123I
OOMeN
H
ONH
OMeO
OMeO
HN NH
O123I
+
t-Butyl Ester Deprotection: Effect of Reaction Time
mV
olts
5 10 15 20 25
Minutes
0
400
13.3
0
500
1500
10.9
0
10.913.3
30
1000
800
5 10 15 20 25
0
400
0
500
1500
030
800MIP-1095 tri-t-butyl ester reference standard
t-butyl deprotection after 35 minutes
Co-injection MIP-1095 and MIP-1095 tri-t-butyl ester reference standards
O
ORNH
O
NH
ORO
O
RO
HN NH
O I
R = H, C(CH3)3
UV-Vis Chromatograms
Purification Optimization for [123I]MIP-1095
A major side product, the des-iodo analog, MIP-1111, was active in vitro
The 1st C18 Sep-Pak removes the majority of Sn side products and unreacted [123I]NaI
The 2nd C18 Sep-Pak separates the desired product, [123I]MIP-1095, from MIP-1111
O
ONH
O
NH
OO
O
O
HN NH
OSnMe3
O
OHNH
O
NH
OHO
O
HO
HN NH
O123I
[123I]MIP-1095
Sn-MIP-1095 Precursor
1. [123I] NaI
O
OHNH
O
NH
OHO
O
HO
HN NH
O H
MIP-1111
+3. TFA/CH2Cl2
O
OHNH
O
NH
OHO
O
HO
HN NH
O123I
[123I]MIP-1095
C18 Sep-Pak2. C18 Sep-Pak
ActiveSide Product
HPLC Analysis: Single Sep-Pak Purification
O
OHNH
O
NH
OHO
O
HO
HN NH
OH
RadioChromatogram
UV-VisChromatogram
5 10 15 20 25 30 35
0
25.6 min
0
20
11.7 min
10
Volts
0.5
1.0
5 10 15 20 25 30 35
Minutes
mVo
lts
[123I]MIP-1095
MIP-1111
O
OHNH
O
NH
OHO
O
HO
HN NH
O123I
HPLC Analysis: Double Sep-Pak Purification
0
0.5
1.0
0
10
20
25.6 min
11.7 min
[123I]MIP-1095
RadioChromatogram
UV-VisChromatogram
O
OHNH
O
NH
OHO
O
HO
HN NH
O123I
O
OHNH
O
NH
OHO
O
HO
HN NH
OH
MIP-1111
5 10 15 20 25 30 3510 15 20 25 30 35
Minutes
Volts
mVo
lts
Effect of Specific Activity on Binding to LNCaP Cells In Vitro
Single Sep-Pak Apparent SA at TOI = 208 mCi/µmol (MIP-1095 + MIP-1111) Double Sep-Pak SA at TOI > 4800 mCi/µmol (MIP-1095)(TOI = Time of Injection)
0
30
60
90
120
No Competitor 10 µM Unlabeled MIP-1095
10 µM PSMA Inhibitor(PMPA)
fmol
bou
nd
Double Sep-PakSingle Sep-Pak
Current Manufacturing Process for [123I]MIP-1095
t-Butyl-123I-MIP-1095 + t-Butyl-MIP-1111
Na123I
H2SO4 C18 Sep-Pak
TFA CH2Cl2
123I-MIP-1095 + MIP-1111 (active)
C18 Sep-Pak
t-Butyl-Sn-MIP-1095
123I-MIP-1095
Peracetic Acid
Direct Binding of [123I]-MIP-1072 and [123I]-MIP-1095 to Prostate Cancer CellsDirect Binding of [123I]-MIP-1072 and [123I]-MIP-1095 to Prostate Cancer Cells
P
O
OHHO COOH
COOH
PMPA
0
50
100
150
200
NoCompetitor
10 uMUnlabeledMIP-1072
10 uMPMPA
0
30
60
90
120
LNCaP (PSMA +)PC3 (PSMA -)
fmol
Bou
nd
123 I-MIP-1072 123 I-MIP-1095
LNCaP (PSMA +)PC3 (PSMA -)
fmol
Bou
ndNo
Competitor 10 uM
UnlabeledMIP-1095
10 uMPMPA
0
50
100
150
200
NoCompetitor
10 uMUnlabeledMIP-1072
10 uMPMPA
0
30
60
90
120
LNCaP (PSMA +)PC3 (PSMA -)
I-MIP-1072 I-MIP-1095
LNCaP (PSMA +)PC3 (PSMA -)
NoCompetitor
10 uMUnlabeledMIP-1095
10 uMPMPA
Saturation Binding to PSMA on LNCaP Cells of [123I]-MIP-1072 and [123I]-MIP-1095 Saturation Binding to PSMA on LNCaP Cells of [123I]-MIP-1072 and [123I]-MIP-1095
MIP-1072 3.8 ± 1.4 1490 ± 62MIP-1095 1.08 ± 0.03 1680 ± 107
Kd (nM) Bmax (fmol/106 cells)
MIP-1095MIP-1072
0.001 0.01 0.1 1 10 100 10000
500
1000
1500
Concentration (nM)
fmol
Bou
nd/1
06ce
lls
MIP-1095MIP-1072MIP-1095MIP-1072MIP-1095MIP-1072
0.001 0.01 0.1 1 10 100 10000
500
1000
1500
Concentration (nM)
fmol
Bou
nd/1
06ce
lls
0.001 0.01 0.1 1 10 100 10000
500
1000
1500
Concentration (nM)
fmol
Bou
nd/1
06ce
lls
Cell Internalization of [123I]-MIP-1072 and [123I]-MIP-1095Cell Internalization of [123I]-MIP-1072 and [123I]-MIP-1095
MIP-1095
0 20 40 60 80 100 1200
500
1000
1500
2000
2500 Total 4C
Total 37CInternalized 4 C
Internalized 37C
Time (min)
fmol
Bou
nd
MIP-1072
0 20 40 60 80 100 1200
400
800
1200
1600
2000Total 4C
Total 37CInternalized 4 C
Internalized 37C
Time (min)
fmol
Bou
nd
Tissue Distribution of [123I]-MIP-1072 in LNCaP Bearing MiceTissue Distribution of [123I]-MIP-1072 in LNCaP Bearing Mice
15 min 1 hr 2 hr 4 hr 8 hr 24 hrTumor:Blood 5 37 65 220 176 411Tumor:Muscle 16 50 70 432 446 64
Time post injection
Blood
Heart
Lungs
Liver
Spleen
Kidneys
Intestin
eSk.M
uscle
Tumor
0
10
20
30
40
15 min1 hr2 hr4 hr8 hr24 hr
40
140
240
%In
ject
ed D
ose/
gram
18 %ID/g
Tissue Distribution of [123I]-MIP-1095 in LNCaP Bearing MiceTissue Distribution of [123I]-MIP-1095 in LNCaP Bearing Mice
15 min 1 hr 2 hr 4 hr 8 hr 24 hrTumor:BloodTumor:Muscle
Time post injection
2 11 24 41 57 1749 49 81 133 121 304
Blood
Heart
Lungs
Liver
Spleen
Kidneys
Intestin
eSk.M
uscle
Tumor
0
10
20
30
40
15 min1 hr2 hr4 hr8 hr24 hr
40
140
240
%In
ject
ed D
ose/
gram
18 %ID/g
Tumor Uptake of 111In-J591, 111In-ProstaScint and 111In-Mouse IgG Bio-Distribution in LNCaP Xenograft MiceTumor Uptake of 111In-J591, 111In-ProstaScint and 111In-Mouse IgG Bio-Distribution in LNCaP Xenograft Mice
Blood Clearance
0
10
20
30
40
0 20 40 60 80
Time (hr)
%ID
/g
Mouse IgGProstaScint111In-J591
Tumor Clearance
0
10
20
30
40
50
60
0 20 40 60 80
Time (hr)%
ID/g
Mouse IgGProstaScint111In-J591
Comparison of Clearance of MIP-1072 and MIP-1095 From Selected TissuesComparison of Clearance of MIP-1072 and MIP-1095 From Selected Tissues
Blood Clearance
0
1
2
3
4
5
0 5 10 15 20 25
Time (hr)
%ID
/g
MIP-1095MIP-1072
Kidney Clearance
0
50
100
150
200
250
0 5 10 15 20 25
Time (hr)
%ID
/g
MIP-1095MIP-1072
Skeletal Muscle Clearance
0
0.3
0.6
0.9
1.2
0 5 10 15 20 25
Time (hr)
%ID
/g
MIP-1095MIP-1072
Tumor Clearance
0
10
20
30
40
50
0 5 10 15 20 25
Time (hr)
%ID
/g
MIP-1095MIP-1072
Tissue Distribution of [111In]-Prostascint in LNCaP Bearing MiceTissue Distribution of [111In]-Prostascint in LNCaP Bearing Mice
Blood
Heart
Lung
s
Liver
Spleen
Kidney
sInt
estin
e Sk.M
uscle
Tumor
0
15
30
45
60 1 hr4 hr24 hr48 hr72 hr
%In
ject
ed D
ose/
gram
0.25 1 2 4 8 24 48 72 (Hours)
Tumor/blood MIP-1072 5 37 65 220 176 411 - -MIP-1095 2 11 24 41 57 174 - -Prostascint - 0.1 - 0.3 - 1 2 3
Tumor/muscle MIP-1072 16 50 70 432 446 64 - -MIP-1095 9 49 81 133 121 304 - -Prostascint - 3 - 12 - 20 31 48
Specific Binding to PSMA is Demonstrated by PMPA Blocking in VivoSpecific Binding to PSMA is Demonstrated by PMPA Blocking in Vivo
Unblocked50 mg/kg PMPA Blocked
Unblocked50 mg/kg PMPA Blocked
LNCaP (PSMA +) Tumor PC3 (PSMA -) Tumor
[123I]-MIP-1072
BloodLungs
Liver
Kidneys
Intestin
eSk.M
uscle
Tumor
0
5
10
15
20
25100
150
200
%In
ject
ed D
ose/
gram
[123I]-MIP-1095
BloodLungs
Liver
Kidneys
Intestin
eSk.M
uscle
Tumor
0
5
10
15
20
2525
100
175
%In
ject
ed D
ose/
gram
Selective Targeting of PSMA In Vivo with [123I]-MIP-1072 and [123I]-MIP-1095 (SPECT/CT 4 hour)Selective Targeting of PSMA In Vivo with [123I]-MIP-1072 and [123I]-MIP-1095 (SPECT/CT 4 hour)
LNCaP
LNCaP
MIP-1072 MIP-1095
Selective Targeting of PSMA In Vivo with [123I]-MIP-1072 and [123I]-MIP-1095 (SPECT/CT at 2 Hours)Selective Targeting of PSMA In Vivo with [123I]-MIP-1072 and [123I]-MIP-1095 (SPECT/CT at 2 Hours)
PC-3 flu(PSMA-)
PC-3 PIP(PSMA+)
PC-3 PIP(PSMA+)
PC-3 flu(PSMA-)
Selective Targeting of PSMA In Vivo with [123I]-MIP-1095 (SPECT/CT)Selective Targeting of PSMA In Vivo with [123I]-MIP-1095 (SPECT/CT)
2 h p.i. 4 h p.i. 24 h p.i.
PC-3 PIP(PSMA+)
PC-3 flu(PSMA-)
Selective Targeting of PSMA with [123I]-MIP-1095 in a Baboon (SPECT/CT 4-6 hr)Selective Targeting of PSMA with [123I]-MIP-1095 in a Baboon (SPECT/CT 4-6 hr)
LNCap
PC3Renal C
ortex
Prostate
Parotid Gland
Renal Corte
x
Prostate
Parotid Gland
Baboon 16100 Baboon 16951
PSMA PSMA
Ex Vivo Binding of [123I]-MIP-1072 and [123I]-MIP-1095 to Human Prostate TissueEx Vivo Binding of [123I]-MIP-1072 and [123I]-MIP-1095 to Human Prostate Tissue
[123I]-MIP-1095[123I]-MIP-1072 H&E Staining
Red = cancerBlue = normalGreen = non-cancer
abnormal
Ex Vivo Binding of [123I]-MIP-1072 to Human Prostate TissueEx Vivo Binding of [123I]-MIP-1072 to Human Prostate Tissue
Prostate Cancer
(#111710B3)
Prostate Cancer
(#117196B1)
Normal Prostate
(#8979C1)
Benign Prostatic
Hyperplasia(#11145A1)
Renal Cortex
(#12001A7)
123I-MIP-1072 + 10 μM cold MIP-1072
[123I]-MIP-1072
123I-MIP-1095 Dipping Study123I-MIP-1095 Dipping Study
Prostate Cancer
(#111710B3)
Prostate Cancer
(#117196B1)
Normal Prostate(#15187F1)
Benign Prostatic Hyperplasia
(#22040B1)
Renal Cortex(#8346A1)
123I-MIP-1095
123I-MIP-1095 + 10 μM cold MIP-1095
Safety Findings for MIP-1072 and MIP-1095Safety Findings for MIP-1072 and MIP-1095
Target dose administered: 10 mCi, < 3 μg, or < 3 nM
Expanded acute rat studyNo adverse effects observed at doses > 300X the human equivalent dose
Cardiovascular effects in conscious dogs (arterial pressure, heart rate and ECG)
No adverse effects observed at doses > 300 times human equivalent dose
General pharmacology screen (NovaScreen™)No effects observed at concentrations up to 1 µM
No stimulatory or inhibitory effects on LNCaP cell growthRadiation dose estimates and starting dose in man were extrapolated from rat tissue distribution study
[123I]-MIP-1072 and [123I]-MIP-1072 Initial Clinical Plan[123I]-MIP-1072 and [123I]-MIP-1072 Initial Clinical Plan
IND recently filed and approvedSingle-blinded, randomized, crossover study in 12 patients with histological confirmed prostate cancer and evidence of recurrent disease10 mCi dose of each, 14 days apartPrimary objective is to evaluate dosimetry, safety, pharmacokinetics, and tissue distribution3 day assessment period
Blood and urine collectionAnterior and posterior planar imagingSPECT/CT
2 week follow-up post 2nd injectionInterim data review once the first 6 patients have been evaluated
[123I]-MIP-1072
[123I]-MIP-1095
Previously Known Lumbar spinal metastatic lesion
Unknown Suspected metastatic lymph node
CT scanalone
Trofex SPECT image (color)
fused withCT scan
Initial Clinical Data with [123I]-MIP-1095Initial Clinical Data with [123I]-MIP-1095
Initial Clinical Data with [123I]-MIP-1095Initial Clinical Data with [123I]-MIP-1095
ConclusionsConclusions
A series of novel halogen-containing glutamate urea heterodimersbased on glutamate-urea-lysine were designed and synthesized
Two lead iodine-containing compounds from this series were identified (MIP-1072 and MIP-1095) that bind with high affinity to PSMA
Both compounds selectively accumulate in PSMA positive human prostate cancer xenografts but exhibit different pharmacokinetics
MIP-1072 and MIP-1095 are currently being evaluated in an exploratory IND and may permit the more accurate diagnosis and staging of prostate cancer, and enable the monitoring of therapy
Preliminary results in humans confirm that MIP-1095 accumulates in metastatic prostate cancer
AcknowledgementsAcknowledgements
MIPKevin Maresca, Ph.DFrank Femia, Ph.DCraig Zimmerman, Ph.DJohn Joyal, Ph.DShawn Hillier, Ph.DJohn Marquis, Ph.DJames Kronauge, Ph.DBrian Abeysekera, Ph.DEd Luss-Lusis, Ph.DNorman LaFrance, M.D.William Eckelman, Ph.DJohn Babich, Ph.D.
Duke UMC P1 human studiesEd Coleman, M.D.Dan George, M.D.
JHU animal imaging studiesMartin Pomper, M.D., Ph.DCatherine Foss, Ph.D