IMAGING with RADIOPHARMACEUTICALS
Functional molecular specificity for disease detection and “follow-up”
Durval C. Costa
MD, MSc, PhD, FRCR
Director
Nuclear Medicine-Radiopharmacology
Champalimaud Clinical Centre
Champalimaud Foundation
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IMAGING
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IMAGES in MEDICINE
(resolution: spatial vs contrast/concentration)
Method
CT
MRI
MRSI
SPECT
PET
HFUS
Optical
Minimum Detectable
Size ( Ø )
1 ~ 2 mm
1 ~ 2 mm
7 mm (~3 mm at 3T)
4 ~ 6 mm
3 ~ 5 mm
< 1 mm
0.02 mm
Minimum Detected
Molar mM pM pM
Cells (n)
400,000
400,000
1,000,000
500,000
300,000
100,000
1000
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IMAGES with RADIOPHARMACEUTICALS
- Cellular functional Specificity -
Fluorodeoxyglucose (FDG) is phosphorylated to FDG-6-PO4 by hexokinase. Since the activity of glucose-6-phosphatase is negligible, FDG-6-phosphate is essentially trapped in tumor cells .
Unfortunately it is also trapped in activated macrophages .
Czernin J and Phelps ME.. Annu Rev Med , 2002; 53: 89-112.
Fluorothymidine (FLT) is phosphorylated by thymidine kinase to FLT-6-PO4 and accumulates in tumor cells.
It is described as a marker of cell proliferation .
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IMAGES with RADIOPHARMACEUTICALS clinical and research applications
 Radiopharmaceuticals for DIAGNOSIS
 Radiopharmaceuticals for THERAPY
 Radiopharmaceuticals for ASSESSMENT and
MONITORING response to THERAPY
 Radioligands for R & D – new THERAPIES
(pharmacokinetics and pharmacodynamics)
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IMAGES with RADIOPHARMACEUTICALS
Case 01
74 y old man;
Radical prostatectomy 10 ys ago for carcinoma;
Bone Scintigraphy – multiple bone metastases;
ULTRASSOUN images – normal, i.e. sem no loco-regional recurrence;
17-July-2006
Alkaline Phosphatase
Acid Phosphatase
Prostatic fraction
125 U/L
4,3 U/L
0,6 U/L
(N 40-150)
(N 0,0-6,5)
(N < 2,6)
PSA (prostate specific antigen)
Proteina C reactiva
0,33 ng/ml (N < 5)
0,4 ng/ml (N 0,0-0,5)
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IMAGES with RADIOPHARMACEUTICALS
Case 01
24-July-2006
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IMAGES with RADIOPHARMACEUTICALS
Case 01
Pathology from biopsy – Thyroid carcinoma; Total Thyroidectomy;
13-November-2006
1st IODO-131 THERAPY
(7,4 GBq, i.e. 200 mCi)
23-July-2007
2nd IODO-131 THERAPY
(7,4 GBq, i.e. 200 mCi)
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RADIOPHARMACEUTICALS
NUCLEAR/MOLECULAR MEDICINE
PET-CT camera
Gama camera
Outpatient
Inpatient
Radiopharmaceuticals
Generators
Radionuclides Cyclotron
Nuclear Reactor
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RADIOPHARMACEUTICALS
NUCLEAR/MOLECULAR MEDICINE
Spatial resolution – detectable minimum lesion size!?
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RADIOPHARMACEUTICALS
Diagnose EARLY to IMPROVE Outcome!
Function
Clinical Ratings
Time
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RADIOPHARMACEUTICALS - PET
Cost-Savings BENEFIT analyses!
Ken A. Miles . An approach to demonstrating cost-effectiveness of diagnostic imaging modalities in
Australia illustrated by positron emission tomography. Australasian Radiology, 2001; 45: 9-18.
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RADIOPHARMACEUTICALS - PET
Cost-Savings BENEFIT analyses!
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PET with FDG in ONCOLOGY
UTILITY in CLINICS
1.
Diagnosis and “grading” of malignant disease
2.
Definition of disease extent staging and restaging
3.
Identification and localisation of disease foci unknown primary (paraneoplastic syndromes)
4.
Evaluation and monitoring of response to therapy
5.
Identification of recurrent disease in comparison with “raising” tumour markers and anatomic/structural changes (CT and MR)
6.
Guide for biopsy
7.
Therapy guidance and “management”
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PET with FDG in ONCOLOGY
Overall results – sensitivity and specificity
1.
Sensitivity - 84% (based on 18 402 patient studies)
2.
Specificity - 88% (based on 14 264 patient studies)
3.
Average management change across all aplications
30% (based on 5 062 patients)
Sensitivity range
Specificity range
Accuracy range
84% - 87%
88% - 93%
87% - 90%
Gambhir SJ, Czernin J, Schwimmer J, et al. A Tabulated Summary of the FDG PET Literature. J Nucl Med, 2001; 42: 1S-93S. [ www.snm.org
]
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RADIOPHARMACEUTICALS
Distinction between TUMOUR and inflammation
21 consecutive pts (3 women and 18 men, age range 41 to 80 y) with suspected squamous head and neck cancer.
FDG
Fluorodeoxyglucose
FDG +ve SCC
Oral cavity
FET +ve
FET
O-(2-[18F]fluoroethyl)-L-tyrosine
FDG +ve Chronic inflammation
Pauleit D, Zimmermann A, Stoffels G, et al. J. Nucl Med, 2006; 47: 251-261.
FET -ve
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RADIOPHARMACEUTICALS
The future requests planning … measures and ACTION
11 C 18 F 3 H 15 O
Cyclotron and “Production Facility”
Molecular Chemistry
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RADIOPHARMACEUTICALS
The future requests planning … measures and ACTION
FDG AC
13 of 22 pts with serum PSA > 3ng/mL had positive AC PET findings.
11 C Acetate
77-y-old man with PSA relapse and serum PSA value of 10.5 ng/mL 8 y after radical prostatectomy and
5 y after salvage external-beam radiation therapy.
Histologic diagnosis showed Gleason score of 8 at surgery. CT scan negative.
Oyama N, et al . J Nucl Med, 44 (4): 549-555; 2003
Only 1 of 24 pts with serum PSA ≤ 3ng/mL had positive findings.
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RADIOPHARMACEUTICALS
… differential diagnosis of DEMENTIA
AD
ROC AD vs Ctr parietotemporal, multiple
(Exatidão = 0.778)
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
Cut off point 0.82
Specificity= 75%
Sensitivity=66%
Cut off point=0.89
Specificity=48%
Sensitivity=84%
0.00
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
1-specificity
FTD
Accuracy = 0.875
ROC FLD vs Ctr frontal, all studies
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
Cut off point 0.76
Specificity= 85%
Sensitivity=76%
Cut off point=0.8
Specificity=68%
Sensitivity=87%
0.00
0.00
0.10
0.20
0.30
0.40
0.50
0.60
1-specificity
0.70
0.80
0.90
1.00
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RADIOPHARMACEUTICALS
… labelling β-Amyloid pathology “in vivo”.
Benzothiazole 11 C - 6-OH-BTA-1
(also known as 11 C - PIB)
Binds to Aβ 1-40 and Aβ 1-42 fibrils
Stilbene 11 C -SB-13
99 Tc m -MAMA-chrysamine G
(analog of Congo red)
Labels Aβ 10-43
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( 18 FAV-45)
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( 18 FGE067)
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( 18 F-BAY94-9172)
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RADIOPHARMACEUTICALS
- positive markers of disease … labelling β-Amyloid pathology “in vivo”.
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N-Methyl11 C-2-(4´-methylamino-phenyl)-6-hydroxy-benzothiazole or 11 C-6-OH-BTA-1
Average radiochemical yield - 20%; Synthesis time - 45 min; Radiochemical purity - 98%.
Ng S, et al.
J Nucl Med 2007; 48: 547-552 .
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RADIOPHARMACEUTICALS
… imaging neuropathology “in vivo”.
KS, 62 y old male; bil. tremor, rigity, akinesia, no falls, no visual hallucinations
H & Y=3.0; MMSE=27/30; CAMCOG=101/107
123 I-FP -CIT
123 I -IBZM pre-synaptic transporter marker dopamine D
2 post-synaptic receptor marker
R
INM
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RADIOPHARMACEUTICALS
… imaging neuropathology “in vivo”.
A D N V E T
Drug induced parkinsonism
IPD
INM INM
DLB
Schizophrenia + PD
AD= Alzheimer’s disease; DLB= dementia with Lewy bodies; ET= Essential benign tremor;
IPD= idiopathic Parkinson’s disease; NV= normal volunteer
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RADIOPHARMACEUTICALS
… in Nuclear Cardiology – Myocardial Viability
Coronary angiography confirms LMS occlusion (A), with patent RCA (B), rightto-left collateral circulation (C) and normal LV contractile function (D)
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RADIOPHARMACEUTICALS
… in Nuclear Cardiology – Myocardial Viability
Patologias associadas
Toxic Autonomous Adenoma of the THYROID
Multiple pulmonary emboli
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RADIOPHARMACEUTICALS
… therapeutic APPLICATIONS
Endocrinology
Hyperthyroidism
Ca Thyroid
IODINE-131
Pheochromocytoma
Paraganglioma
Carcinoid
IODINE-131 - mIBG
Intracavitary
Synovectomy
(microspheres)
YTTRIUM-90
Resistent PAIN
Ca Prostate
Possibly others
STRONTIUM-89
SAMARIUM-153
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