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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. Text. IMAGING clinical practice & research.

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  1. 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 Text

  2. IMAGING clinical practice & research

  3. 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 Cells (n) mM 400,000 400,000 1,000,000 pM500,000 pM300,000 100,000 1000

  4. 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. 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. Czernin J and Phelps ME.. Annu Rev Med, 2002; 53: 89-112.

  5. IMAGES with RADIOPHARMACEUTICALS clinical and research applications • Imaging and Molecular Medicine • Radiopharmaceuticals for DIAGNOSIS • Radiopharmaceuticals for THERAPY • Radiopharmaceuticals for ASSESSMENT and MONITORING response to THERAPY • Radioligands for R & D – new THERAPIES (pharmacokinetics and pharmacodynamics)

  6. 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 125 U/L (N 40-150) Acid Phosphatase 4,3 U/L (N 0,0-6,5) Prostatic fraction 0,6 U/L (N < 2,6) PSA (prostate specific antigen) 0,33 ng/ml (N < 5) Proteina C reactiva 0,4 ng/ml (N 0,0-0,5)

  7. IMAGES with RADIOPHARMACEUTICALS Case 01 24-July-2006

  8. 23-July-2007 2nd IODO-131 THERAPY (7,4 GBq, i.e. 200 mCi) 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)

  9. PET-CT camera Gama camera Outpatient Inpatient Radiopharmaceuticals Cyclotron Generators Radionuclides Nuclear Reactor RADIOPHARMACEUTICALS NUCLEAR/MOLECULAR MEDICINE Diagnosis Therapy

  10. RADIOPHARMACEUTICALS NUCLEAR/MOLECULAR MEDICINE Spatial resolution – detectable minimum lesion size!?

  11. Function Clinical Ratings Time RADIOPHARMACEUTICALS Diagnose EARLY to IMPROVE Outcome!

  12. 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.

  13. RADIOPHARMACEUTICALS - PET Cost-Savings BENEFIT analyses!

  14. PET with FDG in ONCOLOGY UTILITY in CLINICS • Diagnosis and “grading” of malignant disease • Definition of disease extent • staging and restaging • Identification and localisation of disease foci • unknown primary (paraneoplastic syndromes) • Evaluation and monitoring of response to therapy • Identification of recurrent disease in comparison with “raising” tumour markers and anatomic/structural changes (CT and MR) • Guide for biopsy • Therapy guidance and “management”

  15. PET with FDG in ONCOLOGY Overall results – sensitivity and specificity • Sensitivity - 84% (based on 18 402 patient studies) • Specificity - 88% (based on 14 264 patient studies) • Average management change across all aplications • 30% (based on 5 062 patients) • Sensitivity range 84% - 87% • Specificity range 88% - 93% • Accuracy range 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]

  16. SCC Oral cavity FDG +ve FET +ve FDG +ve FET -ve 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 FET O-(2-[18F]fluoroethyl)-L-tyrosine Chronic inflammation Pauleit D, Zimmermann A, Stoffels G, et al. J. Nucl Med, 2006; 47: 251-261.

  17. RADIOPHARMACEUTICALS The future requests planning … measures and ACTION 11C 18F 3H 15O Molecular Chemistry Cyclotron and “Production Facility”

  18. FDG AC RADIOPHARMACEUTICALS The future requests planning … measures and ACTION 13 of 22 pts with serum PSA > 3ng/mL had positive AC PET findings. Only 1 of 24 pts with serum PSA ≤ 3ng/mL had positive findings. 11C-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

  19. RADIOPHARMACEUTICALS … differential diagnosis of DEMENTIA AD FTD Accuracy = 0.778 (Exatidão = 0.778) Accuracy = 0.875 (Exatidão = 0.875)

  20. RADIOPHARMACEUTICALS … labelling β-Amyloid pathology “in vivo”. 18F-florbetapir (18FAV-45) 18F-flutemetamol (18FGE067) 18F-florbetaben (18F-BAY94-9172) Benzothiazole11C - 6-OH-BTA-1 (also known as 11C - PIB) Binds to Aβ 1-40 and Aβ 1-42 fibrils Stilbene11C -SB-13 99Tcm-MAMA-chrysamine G (analog of Congo red) Labels Aβ 10-43

  21. RADIOPHARMACEUTICALS - positive markers of disease … labelling β-Amyloid pathology “in vivo”. 11C-PIB N-Methyl-11C-2-(4´-methylamino-phenyl)-6-hydroxy-benzothiazole or 11C-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.

  22. KS, 62 y old male; bil. tremor, rigity, akinesia, no falls, no visual hallucinations H & Y=3.0; MMSE=27/30; CAMCOG=101/107 123I-FP-CIT 123I-IBZM dopamine D2 post-synaptic receptor marker pre-synaptic transporter marker R Idiopathic Parkinson’s Disease (IPD) RADIOPHARMACEUTICALS … imaging neuropathology “in vivo”. INM

  23. A D N V E T Drug induced parkinsonism IPD DLB Schizophrenia + PD RADIOPHARMACEUTICALS … imaging neuropathology “in vivo”. AD= Alzheimer’s disease; DLB= dementia with Lewy bodies; ET= Essential benign tremor; IPD= idiopathic Parkinson’s disease; NV= normal volunteer INM INM

  24. Coronary angiography confirms LMS occlusion (A), with patent RCA (B), right-to-left collateral circulation (C) and normal LV contractile function (D) RADIOPHARMACEUTICALS … in Nuclear Cardiology – Myocardial Viability

  25. RADIOPHARMACEUTICALS … in Nuclear Cardiology – Myocardial Viability Patologias associadas Toxic Autonomous Adenoma of the THYROID Multiple pulmonary emboli

  26. 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 RADIOPHARMACEUTICALS … therapeutic APPLICATIONS

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