Transcript severin_ISOLDE_users2015x

Decay induced de-chelation of positronemitting electron-capture daughters and its
use in preclinical PET.
G.W. Severin1, L.K. Kristensen2, J. Fonslet1, A.I. Jensen1, C.H. Nielsen2, D.R. Elema1, K. Johnston3,
and U. Köster4
1Hevesy
Laboratory, Center for Nuclear Technologies at the Technical University of Denmark,
Frederiksborgvej 399, 4000 Roskilde, Denmark.
2Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging,
Rigshospitalet and University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
3ISOLDE, CERN, CH-1211 Geneva 23, Switzerland
4Institut Laue-Langevin, 71 avenue des Martyrs, F-38042 Grenoble Cedex 9, France
Receptor-based Positron Emission
Tomography (PET)
• 3-dimensional quantifiable
tomography
•
Used primarily in medical
diagnosis.
•
non-invasive.
•
Requires positron emitting
radionuclides to be covalently
bound to a targeting
molecule(vector).
•
Images like these compel a
transition from diagnositics to
therapeutics
Pfiefer et al. J Nucl Med. 2012 Aug;53(8):1207-15
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Language
”vector”
”chelate”
”radiometal”
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Imaging-to-Therapy
•
If we can find cancer can we
also treat it using the same
vectors?
•
Use vectors for drug
delivery-
•
Drug-loaded nanoparticles
•
Radionuclides
Can we make a PET technique to determine
if therapeutic
• (Auger emitters)
agents are internalized or not?
Work best if ‘internalized’
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”Internalization”
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Small modifications change internalization
status
(DOTA)TATE
Internalizes
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(DOTA)LM3
Doesn’t Internalize
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Imaging-to-Therapy
•
If we can find cancer can we
also treat it using the same
vectors?
•
Use vectors for drug
delivery-
•
Drug-loaded nanoparticles
•
Radionuclides
Can we make a PET technique to determine
if therapeutic
• (Auger emitters)
agents are internalized or not?
Work best if ‘internalized’
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Enter ISOLDE
134Ce
and
140Nd
3.2 d
Nearly identical
decay schemes to
‘short-lived’
positron emitting
daughters.
EC
6.5 m
QEC = 380 keV
134
Match perfectly
with DOTATATE
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Ce
3.4 d
EC
3.4 m
La
140
Nd
QEC = 444 keV
140
64% β+
36% EC
Nearly identical
lanthanide
Electron
chemistry.
Difficult to
produce and
purify, except at
ISOLDE.
134
Eave β+= 1.22 MeV
QEC gs-gs= 3.73 MeV
Pr
51% β+
49 % EC
Eave β+= 1.07 MeV
QEC = 3.34 MeV
E.S.
Branch 5%
Capture Decay is special, chemically.
γ 605 keV
140Nd
stable
134
Ba
DTU Nutech, Technical University of Denmark
stable
140
Ce
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140Nd
EC decay creates
140Pr
with an atomic hole
that stabilizes by electron transitions
which kick off more e-’s (Augers) and make more holes
ultimately giving an Auger Cascade (e-’s:10eV-50keV)
140
140Nd
Pr
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The result of EC decay with our vector:
140Pr
140
Nd
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3 minute t1/2 clock begins ticking.
β+
140Pr
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3 minute t1/2 clock begins ticking.
140Nd
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3 minute t1/2 clock begins ticking.
β+
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Consequenses of the hypothesis
•
140Nd
DOTATATE (internalizing) will give a PET signal that is localized on
tumors (or cells expressing the receptor).
• 140Nd DOTALM3 (non-internalizing) will give a redistributed PET signal.
• Experimental procedure: Inject mice which have sst2+ tumors with each
construct and compare the images when pre- and post- mortem (after
‘equilibration’ of the tracer distribution)
Living PET
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Post-Mortem PET
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Results: Post-Mortem Biodistribution
(parent distribution)
Pancreas can give a
clean signal of the noninternalizing tracer
Internalizing tracer
clears very rapidly, and
does not accumulate in
the tumor
Free-ion lanthanides
also accumulate in the
tumor! (and Liver is a
‘sink’ organ)
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Cross your eyes: Tumor ratio (16h/PM)
Tumor signal ratio: 16h/PM
1.2
1
0.8
0.6
0.4
Non-internalizing
(DOTALM3)
Internalizing
(DOTATATE)
Control
(NdChloride)
0.2
0.89±0.13
1.02±0.11
1.02±0.11
0
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PET study: Non-Internalizing (DOTALM3)
16h = daughter distribution
Post-Mortem = parent distribution
16 hours
Post-Mortem
3 % ID/g
”Source”
0 % ID/g
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”Sink”
Kidney
Liver
DOTALM3
0.78 ± 0.03
3.13 ± 0.82
DOTATATE
0.87 ± 0.10
1.29 ± 0.33
NdChloride
0.68 ± 0.03
0.96 ± 0.03
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Reset the scale, and you can see the
pancreas: Non-Internalizing DOTALM3
16 hours
8%
ID/g
Ratio(16h/PM):
0.44±0.08
0%
8ID/g
%
ID/g
Post-Mortem
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0%
Conclusions
• With careful optimization, internalization status might be determined
using 140Nd or 134Ce PET.
• Requires high specific activity (at least in the sstr2 system)
• Determining the diffusion rates will depend upon having both 134Ce and
140Nd in high yield.
• Next steps: use a better perfused tumor model; introduce a ‘washout’
injection; triple coincidence w/44Sc (?).
Thank you for your attention!
Thanks to the behind-the-scene contributors at ISOLDE!
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