Download New PET radiopharmaceuticals

ISCORN, Mikulov, May 11-14, 2010 Czech Republic
New PET radiopharmaceuticals:
targeting the L-amino acid transport
system in prostate cancer
Jørgen Frøkiær
Department of Clinical Physiology and Nuclear Medicine
Aarhus University Hospital - Skejby
Aarhus University, Denmark
[email protected]
Agenda
Prostate cancer epidemiology in brief
How is prostate cancer diagnosed – biomarkers?
Which diagnostic modalities does nuclear medicine provide?
Why target the L-amino-acid transport system?
Development of and experience with novel tracers
Next steps
Cancer incidents in Danish males (2006)
Prostate cancer epidemiology in brief
How is prostate cancer diagnosed – biomarkers?
Staging of prostate cancer
Which diagnostic modalities does nuclear medicine provide?
Why target the L-amino-transport system?
Development of novel tracers
Next steps
Prostate cancer in Danish males (2006)
Prostate cancer epidemiology in brief
How is prostate cancer diagnosed – biomarkers?
Staging of prostate cancer
Which diagnostic modalities does nuclear medicine provide?
Why target the L-amino-transport system?
Development of novel tracers
Next steps
How is prostate cancer diagnosed?
PSA and other biochemical biomarkers (screening)
Symptoms (LUTS, back pain etc…)
Rectal examination
Biopsi proven verification
Molecular imaging ??
Prostate cancer modality time trend
analysis from 1973-2004 (USA)
Jani B. et al. Am J Clin Oncol 2010
No early mortality benefit from annual
prostate cancer screening (USA)
Andriole GL et al. NEJM, March 26 2009
..Some additional facts about prostate cancer
Prostate cancer is the most common malignancy in men
comprising 33% of newly diagnosed cancers in the United
States.
Accurately detecting the presence of disease CONFINED to
the prostatic bed versus that of that of extraprostatic spread to
lymph nodes or the skeletal system has profound treatment
implications.
Ultrasound, MRI and CT may only be useful for local T staging
THUS - there is currently no definitive imaging technique in
the initial staging and restaging of prostate carcinoma.
Nuclear Medicine Imaging in Prostate Cancer
Molecular imaging with 111-In-Capromab pendetide does not
demonstrate sufficient sensitivity.
Prostate cancer cells has a low ability to take up 18-F-FDG and
is not appropriate for clinical use. Urine excretion!
PET tracers including 11-C-acetate, 11-C-choline, 11-Cmethionine and 18-F-fluorocholine may characterize different
metabolic aspects of prostate carcinoma.
Nuclear Medicine Imaging in Prostate Cancer
Molecular imaging with 111-In-Capromab pendetide does not
demonstrate sufficient sensitivity.
Prostate cancer cells has a low ability to take up 18-F-FDG and
is not appropriate for clinical use. Urine excretion!
PET tracers including 11-C-acetate, 11-C-choline, 11-Cmethionine and 18-F-fluorocholine may characterize different
metabolic aspects of prostate carcinoma.
Thus there is a need for a better radiotracer
with little of no urinary excretion for the evaluation
and staging of patients with prostate carcinoma
Development of L-Amino Acids analogs for PET
Background
In the 90´ies the metabolically active amino acid L-methyl-11Cmethionine was used clinically to distinguish malignant tissue
from normal tissue or benign growths in the brain with PET.
L-Amino Acid Transporter-1 (LAT-1) is mainly expressed in
fetal tissue and cancer cells corresponding to a so-called
oncofetal antigen.
The movement of the naturally occuring amino acids such as
L-leucine and L-methionine across tumor cell membranes
occurs predominantly through carrier mediated transport by
the sodium-independent LAT-1
General molecular structure of ATs
PALACIN, M. et al. Physiol. Rev. 78: 969-1054 1998
Synthesis of the first synthetic L-amino acid analogs
Synthesis of 18F-FMACBC and 18F-FACBC
Superior uptake of the anti-analogue
at late time points in rat brain tumor
Shoup TM et al. JNM 40:331-338, 1999
Martarello L et al. J Med Chem 45:2250-59, 2002
Synthesis of the first synthetic L-amino acid analogs
Synthesis of 18F-FMACBC and 18F-FACBC
Superior uptake of the anti-analogue
at late time points in rat brain tumor
SELECTION OF
ANTI-18F-FACBC
AS LEAD COMPOUND
Shoup TM et al. JNM 40:331-338, 1999
Martarello L et al. J Med Chem 45:2250-59, 2002
Biodistribution shows superior activity ratio of
FACBC compared with FDG in tumor-bearing rats
18F-FACBC
Shoup TM et al. JNM 40:331-338, 1999
18F-FDG
Biodistribution shows superior activity ratio of
FACBC compared with FDG in tumor-bearing rats
18F-FACBC
Shoup TM et al. JNM 40:331-338, 1999
18F-FDG
Intense tumor uptake of 18F-FACBC in the brain
MRI GdDTPA
(pre-surgery)
FDG
(8 wk post)
FACBC
(1 wk post)
Shoup TM et al. JNM 40:331-338, 1999
Experience with 18F-FACBC based on initial
studies in tumor-bearing rats and human
There is a marked uptake of 11F-FACBC in the brain of rats
with 9L gliosarcoma.
High tumor accumulation of 11F-FACBC in a patient with
glioblastom multiforme.
High tumor to brain ratio suggest that 11F-FACBC is a
potentially valuable agent for the diagnosis of metastatic
disease in humans by PET.
Anti-18F-FACBC for prostate cancer detection
Basic conditions for preclinical experiments:
Prostate cancer cells are slow growing
Need a tracer with no or low urinary excretion
Proper cell lines available for testing
Good animal models available for testing uptake in tumor cells
Anti-18F-FACBC has a higher affinity for DU145*
than for 18F-FDG
Presence
Absence
of natural amino acids and D-glucose in medium
*DU 145 PCa is an androgen independent human
prostate cancer cell line
Oka S et al. JNM 48:46-55, 2007
Biodistribution of anti-18F-FACBC compared with
18F-FDG in the OPCT* rat model
*OPCT is a rat model with orthotopic prostate cancer transplanatation
Oka S et al. JNM 48:46-55, 2007
Biodistribution of anti-18F-FACBC compared with
18F-FDG in the OPCT* rat model
*OPCT is a rat model with orthotopic prostate cancer transplanatation
Oka S et al. JNM 48:46-55, 2007
Higher contrast of anti-18F-FACBC than 18F-FDG in
the OPCT rat model by autoradiography
A + B) FACBC
C + D) FDG
Oka S et al. JNM 48:46-55, 2007
Dynamic micro-PET study of anti-18F-FACBC
and 18F-FDG in the OPCT rat model
FACBC
FDG
Oka S et al. JNM 48:46-55, 2007
Superior discrimination of tissue inflammation with
anti-18F-FACBC than with 18F-FDG in the DPCI rat
*DPCI is a rat model with benign prostate hypertrophy
Oka S et al. JNM 48:46-55, 2007
First clinical proof of concept study with
anti-18F-FACBC for prostate cancer detection
Eight patients underwent dynamic prostate PET-CT imaging
Good correlation of local FACBC uptake with either sextant
biopsy or histology of the surgically removed prostate
Two patients with malignant lymph nodes had intense uptake
correspondingly
In correlation of lymph node status, 7 of 9 patients had
excellent concordance of anti-18F-FACBC pelvic nodal
findings with clinical follow-up.
Schuster DM et al. JNM 48:56-63, 2007
Coronal PET and CT fused anti-18F-FACBC images
from 63 y-old male with bilateral prostate carcinoma
Schuster DM et al. JNM 48:56-63, 2007
Representative time-activity curve showing rapid
uptake of anti-18F-FACBC in prostate carcinoma
Schuster DM et al. JNM 48:56-63, 2007
Extensive invasive prostate carcinoma with uptake
of anti-18F-FACBC in left iliac lymph nodes
Schuster DM et al. JNM 48:56-63, 2007
Restaging of biopsy proven prostate carcinoma with
uptake of anti-18F-FACBC in prostate bed
PET
Schuster DM et al. JNM 48:56-63, 2007
CT fused
Uptake in prostate bed
Schuster DM et al. JNM 48:56-63, 2007
Is LAT-1 a novel biomarker in PC?
1)
Identify whether LAT-1 is a true specific biomarker for
prostate cancer by
Comparing LAT-1 with Ki-67 labelling
Comparing with the Gleason score
Molecular structure of L-Amino Acid Transporter-1
(LAAT1 = SLC7A5)
Extracellular
Plasmamem
Intracellular
Sakata T. et al. Pathol Int. 2009 Jan;59(1):7-18.
Characterization of LAT-1 in prostate cancer
A) Generation of higly specific monoclonal ab´s
Extracellular
Plasmamem
B) Immunohistochemistry of prostate biopsies
Intracellular
Sakata T. et al. Pathol Int. 2009 Jan;59(1):7-18.
Experience with anti-18F-FACBC in renal cancer
Since anti-18F-FACBC has shown this excellent uptake within
primary and metastatic prostatic carcinoma with very limited
renal excretion compared with FDG
Anti-18F-FACBC may therefore be helpful in detecting and in
the preoperative differentiation of the more aggressive clear
cell renal cell carcinoma from that of the less agressive
papillary carcinoma.
Hyper-cortical uptake of anti-18F-FACBC
Axial CT
PET
Fused image
Iso-cortical uptake of anti-18F-FACBC
Axial CT
PET
Fused image
Role of anti-18F-FACBC in renal cancer?
Anti-18F-FACBC did not prove useful in visualizing clear cell
renal cell carcinoma but in the few cases demonstrated better
conspicuity for papillary cell tumors.
In order to determine if anti-18F-FACBC may have some utility
in determining preoperatively if a lesion is a papillary cell
subtype, a larger series would be necessary.
Initial experience with anti-18F-FACBC
Imaging with anti-18F-FACBC demonstrates uptake in both
primary and metastatic prostate carcinoma on initial staging
as well as uptake in recurrent prostate carcinoma within the
prostate bed, lymph nodes, and bone.
Anti-18F-FACBC PET/CT has succeeded in identifying
neoplastic foci, even when other tracers were negative,
Anti-18F-FACBC was instrumental in directing biopsy to prove
neoplastic recurrence in one patient in whom lymph nodes
were not obviously enlarged.
Next step with anti-18F-FACBC
The IPR for the compound has been acquired by GE
Larger POC trials are needed for establishing a definite role of
anti-18F-FACBC in prostate cancer
Thank you for your attention