IPET 2015 International Conference on

Clinical PET-CT and Molecular Imaging Vienna, Austria, 5-9 October 2015

Clinical PET in Neurology/Neurosurgery

Jun Hatazawa, MD, PhD

Osaka University Graduate School of Medicine Department of Nuclear Medicine and Tracer Kinetics

PET Molecular Imaging Center Immunology Frontier Research Center

Topics IPET 2015

Boron Neutron Capture Therapy for brain tumors: what is BNCT? Alzheimer’s disease: who should be treated by Donepezil hydrochloride? Chronic brain ischemia: who should be treated by bypass-surgery?

IPET 2015

Boron Neutron Capture Therapy (BNCT) for Malignant Tumors

How to produce neutron beam How to deliver Boron-10 to cancer cell How to evaluate Boron-10 accumulation in cancer and normal tissue by PET

BNCT is based on in vivo nuclear reaction between neutron and Boron-10, Boron-10 delivery to cancer cells, and evaluation of Boron-10 accumulation by PET.

Principle of Boron Neutron Capture Therapy

BNCT is tumor-cells targeted radiotherapy that significantly increases the therapeutic ratio relative to conventional radiotherapies(1,2,3).

1. Slakin D.N.,et al. Brain. 1991;114: 609–29. 2. Barth, R.F., et al. Cancer. 1992; 2995–3007. 3. Kato I., et al. Applied Radiation and Isotopes. 2004; 61: 1069–73.

Tumor cell

thermal neutron

Boron (10B) α particle

7Li particle

4

IPET 2015

4µm

9µm

From Reactor to Accelerator

照射系サイクロトロン

治療系

ビーム輸送系

9000

12800

サイクロトロン

ビーム輸送系

照射系

治療系

1H 9Be (p, n) 9B

9Be

1n

IPET 2015

cyclotron Target and modulator

Patient bed

Beam transport

Patient bed

Target and modulator

cyclotron

Beam transport

COOH NH 2

CH CH 2

HO

HO 10 B

F 18

COOH NH 2

CH CH 2

HO

HO 10 B

COOH NH 2

CH CH 2

2-[F-18]Fluoro-4-borono-L- Phenylalanine (18FBPA ) (microdose, ~1mg/kg)

4-borono-L-phenylalanine (BPA) (therapeutic dose, 500mg/kg)

L-phenylalanine (PA)

Ishiwata K, Shiono M, Kubota K, Yoshino K, Hatazawa J, Ido T, Honda C, Ichihashi M, Mishima Y. Melanoma Res. 2:171-179, 1992

boron carrier used for therapy

imaging probe used for PET

Delivery of Boron-10 to Cancer Cells IPET 2015

Cancer-specific FBPA PET Imaging

COOH

NH 2

CH CH 2

HO

HO

10 B

F 18 2-[F-18]Fluoro-4-borono-L- Phenylalanine (18FBPA )

x200

RGC-6 tumor cell transplantation

Telepine-oil induced inflammation

Ishiwata K, et al. Melanoma Research, 1992

Wongthai P, Hagiwara K, Miyoshi Y, et al. Cancer Sci. Mar 2015;106(3):279-286

Watabe T, et al. Evaluation of 18F-FBPA as a tumor specific substrate of L-type amino acid transporter 1 (LAT1): in vitro cellular uptake analysis and in vivo PET compared to 18F-FDG and 11C-Methionine (in preparation)

IPET 2015

FBPA PET FBPA PET

Inductively coupled plasma - optical emission spectroscopy

Hanaoka K, Watabe T, Naka S, et al. FBPA PET in boron neutron capture therapy for cancer: prediction of B concentration in the tumor and normal tissue in a rat xenograft model. EJNMMI Res. Dec 2014;4(1):70

FBPA PET predicts BPA accumulation in Tissue IPET 2015

RGC-6 tumor cell transplantation

Recurrent Oligoastrocytoma

T2WI T1WI(CE+) PET/CT PET

9 T/N ratio 7.7, T/B ratio 7.3

IPET 2015

FBPA PET (60min after injection)

FBPA uptake value tumor：1.9 normal：0.9 myocardium：1.3 T/N ratio 2.1 T/B ratio 1.5

Radiation Necrosis IPET 2015

FBPA PET (60min after injection)

Kawabata S, Miyakate S, Nonoguchi N, et al. Applied Radiation and Isotopes 2009；67：S15-S18

Prognosis after BNCT IPET 2015

RCNP, Osaka Univ

before after Parotid gland malignant tumor

Kato I, et al.,Applied Radiation and Isotopes 61；1069-1073：2004

Neutron Irradiation accelerator

Boron Neutron Capture Therapy

COOH

NH 2

CH CH 2

HO

HO

10 B

F 18

COOH

NH 2

CH CH 2

HO

HO

10 B

4-borono-L-phenylalanine (BPA) (therapeutic dose, 500mg/kg)

2-[F-18]Fluoro-4-borono-L- Phenylalanine (18FBPA ) (microdose, ~1mg/kg)

IPET 2015

Summary of BNCT and PET

IPET 2015

Phase II Clinical trials of Cyclotron-based BNCT for brain tumor and head&neck cancer are conducted now in Japan. FBPA PET has critical role for selection of appropriate patients. The cost of installing BNCT Center including PET was around 30M Euro.

Signal from basal forebrain

Cortical neurons

Acetylcholine Neural Transmission System

acetylcholine

acetylcholine esterase

acetylcholine receptors

IPET 2015

Acetylcholine esterase inhibitor is prescribed to AD patients to increase acetylcholine concentration in synapses.

Acetylcholine Receptor Imaging normal young (25 y.o.) normal aged (75 y.o.)

Alzheimer’s disease (72 y.o.)

IPET 2015

11C-3NMPB

Residual Muscarinic Acetylcholine Receptors

Effect of choline esterase inhibitor “Donepezil” is expected when Ach receptors are residual.

effective not effective

MCI AD AD advanced

IPET 2015

11C-3NMPB

0

CBF 80ml/100ml/min CMRO2 6ml/100ml/min OEF 70% CBV 15ml/100ml CMRO2

(15O2)

CBF (H2

15O)

OEF (15O2/H2

15O)

CBV (C15O)

CBF and CMRO2 PET in humans IPET 2015

Early arterial phase

Left MCA embolic occlusion (3 hours of onset)

IPET 2015 Acute Embolic Occlusion late arterial phase

Cerebral blood flow Cerebral oxygen consumption

Acute Embolic Occlusion

Brain energy metabolism is maintained in first 6 hours. Shimosegawa E, et al.“Metabolic Penumbra in Acute Brain Infarction: a correlation with Infarct growth” Ann Neurol 2005;57:494-505

IPET 2015

Intravenous administration of tissue plasminogen activator within 3 hours onset improved patient outcome.

% of good outcome at 3 months t-PA placebo

NIH Stroke Scale Barthel Index

31% 20% 50% 38%

N Engl J Med 1995;333:1581-7

Thrombolytic Therapy IPET 2015

Misery perfusion (high OEF): a predictor of future onset of ischemic stroke

Yamauchi H, Fukuyama H, Nagahanma Y, Et al. Significance of increased oxygen extraction fraction in fove-year prognosis of major cerebral arterial occlusive disease. J Nucl Med 1999; 40:1992-1998

Recurrence probability in 5 years: High OEF 70% Normal OEF 20%

Grubb RL, Derdeyn CP, Fritsch SM, et al. Importance of hemodynamic factors in the prognosis of symptomaticcarotid occlusion. JAMA 1998; 280:1055-1060 (Class I)

IPET 2015

EC-IC Bypass Surgery High OEF patients: n=21 Mean follow-up period: 7.3 year（5～13 year） Death: 2 case ( 7and 8 years after surgery) Stroke: 5 cases (23% onset)

CBF CBV OEF CMRO2

CBF CBV OEF CMRO2

術前

術後

Angiography CT

IPET 2015

IPET 2015 Summary

Clinical PET study in CNS diseases is used to select patients who will have a benefit of new treatments. NM is a field of integration of science. Nuclear physics, chemistry, pharmacology, medical engineering, material science, computer science, informatics, and molecular physiology are the main components. NM promotes medical innovation for patients care by providing molecular pathology of diseases, by evaluating therapy effects, and by evaluating new treatment.