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EMIM congres Leiden JMV
Citation preview
SPECT/CT imaging of prostate cancer xenografts using a new bombesin
receptor antagonist
Molecular Radiopharmacy
L.M. van der Graaf1, T. Maina2, P.J. Marsouvanidis2, M. Melis1, S.C. Berndsen1, E.P. Krenning1, J. Martinez3, L. Brunel3, J. Fehrentz3,
B.A. Nock2, M. de Jong1
1Erasmus MC, Rotterdam, Netherlands, 2NCSR “Demokritos”, Athens, Greece, 3Faculté
de Pharmacie, CNRS-Universités de Montpellier 1 et 2, Montpellier, France
Introduction
Bombesin analogues bind GRP-receptors
overexpressed on prostate cancer and breast
cancer
Proof of concept obtained clinically: AMBA, MP2248Different structures/linkers/radionuclides: All targeting GRPR
Agonists, disadvantages: High bioactivity (side effects) High pancreatic uptake (problems during PRRT)Mitogenic effects
Introduction Antagonists: affinity, no bioactivity, less internalization
We have always believed, antagonists would not work for
imaging and radionuclide therapy
However:
- [99mTc]Demobesin 1: Maina et al, Eur J Nucl Med Mol Imaging,
2003; Reubi et al, J Nucl Med,2008
- RM2: Maecke et al, Eur J Nucl Med Mol Imaging, 2011
J Martinez et al. compounds (JMV): J. Med. Chem. 2000, 43, 2356-2361, Peptides, 1998, 19, 57-63
- DOTA coupled to JMV594: JMV4168 (JMV)
Aim
Evaluate JMV versus AMBA in the PC3-model• In vitro: receptor affinity, antagonistic properties, internalization• In vivo biodistribution in SCID and Nu/Nu mice, 111In vs. 177Lu,
PC-3: commonly used
PC-295: more physiological• In vivo stability• In vivo nanoSPECT/CT
JMV4168
Results:GRP receptor affinity
IC50 JMV: 1.3 nM versus 0.7 nM for AMBA
IC50 JMV & AMBA
-14 -12 -10 -8 -6 -40
50
100
150
111In-JMV+JMV111In-AMBA+AMBA
Log block (M)
% b
ind
ing
Competitive antagonistBinds the same binding site on the receptor
Results:Internalization, 60 min, 37°C in PC3
Results: in vivo biodistribution- 111In in male Nu/Nu mice
4h p.i. PC3 vs PC295
1 MBq/mouse; 10 pmol
Results:in vivo biodistribution- 111In in SCID mice with PC3 xenograft
111In-JMV4168
1 MBq/mouse; 10 pmol
Results:in vivo biodistribution- 177Lu in SCID mice with PC3 xenograft
1 MBq/mouse; 10 pmol
ResultsScintigraphy, NanoSPECT/CT
4h p.i.
24h p.i.
1h p.i.
17-20 MBq 111In-JMV, 250 pmol,Scanning time 26 min Pinhole: 1.4 mm
ResultsDynamic nanoSPECT/CT
Time activity curve
Antagonists: very interesting approach, less side effects
JMV: High tumor uptake
JMV: retention in tumor not as good as agonist, excellent
for short-lived radionuclides
Pancreas low: tumor/pancreas ratio much better than for
agonist!
Future outlook:
Stabilized compounds
Dimers: better retention in tumor?
Radionuclide therapy to erradicate tumors
Conclusions
Uptake in PC3 cells Athens vs Rotterdam
Culture media: - DMEM+ pyruvate+FBS+p/s - RPMI+FBS +p/s
Incubation: 2 hours at 4°C
JMV
Rd
am
DM
EM
blo
ck
Rd
am
RP
MI
blo
ck
Ath
ene
DM
EM
blo
ck
0
5
10
15
%D
/mg
eiw
it
MP2248
Rd
am D
ME
M
blo
ck
Rd
am
RP
MI
blo
ck
Ath
en
e D
ME
M
blo
ck
0
5
10
15
%D
/mg
eiw
it
JMV
Rd
am
DM
EM
blo
ck
Rd
am
RP
MI
blo
ck
Ath
ene
DM
EM
blo
ck
0
2
4
6
8
10
%D
MP2248
Rd
am D
ME
M
blo
ck
Rd
am
RP
MI
blo
ck
Ath
ene
DM
EM
blo
ck
0
2
4
6
8
%D
Results:metabolites [177Lu]JMV4168
mouse urine, 30 min pi
Parent, 0%
Metabolite A, 49%
Metabolite B, 51%
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