Multimodal imaging;

Combining PET, SPECT with CT, MRI, Optical and Ultrasound

Joost Haeck

AMIE coordinator (amie@erasmusmc.nl)

J.Haeck@ErasmusMC.NL

Short recap

• SPECT and PET imaging makes use of radioactivity

• Radioactivity is coupled to, or incorporated in molecules through radiochemistry

• The molecule determines where the radioactivity ends up

• SPECT: single photon emission computed tomography

γ-emitters: ~100-300 keV

e.g. 99mTc, 111In, (177Lu)

• PET: positron emission tomography

positron emitters 2 photons of 511keV

e.g. 18F, 68Ga

Radionuclide / Molecular imaging

• SPECT and PET: tracers

• ligands

• (deoxy)glucose

• hormones

• vitamins

• RGD, VEGF-R

• amino acids

• nanoparticles

Radionuclide / Molecular imaging

Non-targeted

Targeting Nuclear Medicine

IMAGING

AND

THERAPY

• SPECT and PET: functional in vivo imaging

• glucose-/ oxygen-metabolism

• receptor density (e.g. hormone, vitamin)

• protein concentration

• DNA synthesis

• apoptosis

• angiogenesis

• etc.

Radionuclide / Molecular imaging

• Pharmacology

• Oncology

• Inflammation / infection

• Cardiology

• Neurology, psychiatry

• Nephrology

• Biology, physiology

• Etc.

PET and SPECT imaging applications

PET image

Glucose and [18F]FDG

• Glucose

[18F]FDG

Glucose and [18F]FDG

•Glucose ATP

•Metabolic active cells:

•High glucose consumption

•High cell turnover:

•High glucose consumption!

Scientific Electronic Library Online

Determine MRglu

“Baseline” mouse (no tumor)

PET imaging and anatomical information

• CHALLENGE

• Short imaging time (dynamic studies)

• Physiological conditions determine metabolism (PET)

• Anatomical reference – Where is the signal coming from

• STRENGTH

• Non-invasive, 3D whole body

• Ultra high sensitivity (pM-nM)

• Tracer quantities (no pharmacological effect)

• Quantitative (over time)

• Early in disease process

• WEAKNESS

• Limited spatial resolution

• Poor anatomic detail

Animal SPECT and PET

Biodistribution study

Courtesy: Dr. T. Maina-Nock

• STRENGTH of imaging studies

Reduction of number of animals needed

PET vs SPECT

Advantages of PET:

• higher sensitivity

• use of physiological tracers

• better quantification

• less noise

Advantages of SPECT:

• higher resolution

• tracers: longer half-lifes cheaper

more widely available

• multiple labelling studies

PET SPECT

Resolution 2 mm <1 mm

Sensitivity pmol nmol

Quantification ++ +

Tracer half-lives sec’s, hr’s hr’s, days

Tracers Physiologic Modified

Modified Physiologic

Early kin. (min) +++ +

Late kin. (days) +/- ++

Spatial resolution animal PET vs SPECT

0.5

mm

0.6

mm

0.75

mm

0.35

mm

0.4

mm

0.45

mm

Animal SPECT

Animal PET: 1-2 mm

Overview • Applications:

– Heart

– Brain

– Infection and immunity

– Oncology

• From imaging to therapy

• Renal clearance

– Challenges and Pitfalls

Cardiovascular

Courtesy: CellCyte Genetics Kirkland, WA

Stem cell trafficking using dual-isotope imaging

99mTc-Cardiolite

111In-oxyquinoline

99mTc-sestamibi: myocardial perfusion 111In-labeled stem cells: engraftment in an infarcted heart

Heart imaging

Infarcted Heart

96h after injection

99mTc-sestamibi 99mTc-sestamibi

111In-oxyquinoline

99mTc-sestamibi

Heart imaging 18F-FDG-PET:

Reduction of defect in an

infarcted heart by infusion

of stem cells

Heart anatomy and function

• MRI CT

Heart anatomy and function

Brain / neurosciences

Comparison of binding of 11C-PIB, 18F-FPIB and 18F-BF-168 to

sections of temporal cortex of human brain tissue to detect

amyloid plaques

Svedberg et al., NM&B 2012

Neurosciences

Alzheimer's disease

Healthy control

C.Baltes et al. 2010

Neurosciences - MRI

Oncology

Small animal imaging in oncology

Detection (primary and metastases)

Pharmacokinetics and dosimetry (imaging,therapy)

Microdosimetry (kidneys, tumors)

Tumor response over time

Normal organ function over time

18F-FDG PET

Dandekar M et al. JNM 2007

Deoxyglucose analogue metabolic rate

Xenografted nude mice:

• 4h fasting before injection

• 7 min scan, 60 min p.i.

(anesthesia and heated bed)

Fluorothymidine assess cell proliferation

Xenografted nude mice:

18F-FLT PET

Waldherr et al.

General structure of a radiopeptide:

Tumour receptor targeting

• Somatostatin receptor neuroendocrine tumours

• Gastrin receptor MTC, SCLC

• Bombesin receptor prostate, breast

• etc.

radionuclide linker peptide

receptor

(tumours)

Development of radioligands:

Obtain high tumour yet low normal tissue uptake/binding

Tumour receptor targeting

Comparative SPECT/CT study of 12 111In-gastrin analogues

SPECT/CT of CA20948 rat tumour

(111In-octreotide/octreotate)

tumour

tumour

adrenals

lung metastases

SPECT/CT of CA20948 rat tumour

(111In-octreotide/octreotate)

tumour

tumour

adrenals

Dynamic tumor uptake

0

2

4

6

8

10

12

14

0 10 20 30 40 50 60 70

Time [min]

Acti

vit

y i

n t

he t

um

or

[MB

q]

Kinetics of tumour uptake

Dynamic image of a mouse • 70 MBq 111In-labeled SST analog

• 29 scans, 2 minutes each

• Total scan time: 1 hour

SPECT/CT of PC3 xenografts (111In-bombesin)

Sagittal Coronal Transversal

Inhomogeneous tumour uptake: microdosimetry

No receptor expression, necrosis or low perfusion?

From imaging to targeted radiotherapy

radionuclide linker peptide

receptor

(tumours)

Diagnostic Imaging:

SPECT: 111In, 99mTc

PET: 68Ga, 64Cu, 94mTc

Radionuclide therapy:

90Y, 67Cu, 111In, 177Lu, 188Re, 213Bi

177Lu DOTA octreotate

SSTR2

Somatostatine analogues:

Peptide Receptor Radionuclide Therapy

(PRRT)

molecular imaging therapy

nostics thera-

From imaging to targeted radiotherapy

177Lu-DOTA-Octreotate Therapy

Paraganglioma

1st Therapy

2nd Therapy

3rd Therapy

Sequential SPECT/CT after 74 MBq 177Lu-octreotate/0.4µg)

3h 24h = d1 d2 d4 d7 d11

177Lu-DOTA-Octreotate Therapy (mice)

Quantification of 177Lu-tumour uptake dosimetry (~100Gy)

Renal clearance

99mTc-DMSA SPECT/CT after PRRT

-1 d d50 d100 d147

y = 1.0587x + 1.1774

R2 = 0.9459

0

5

10

15

20

25

0 5 10 15 20 25

Gamma-counter [%IA left kidney]

SP

EC

T [%

IA left k

idney]

Kidney tracer: normal uptake ~20% ID/g

Quantification of 99mTc-DMSA

renal uptake

Functional parameter

Forrer et al. EJNMMI 2007

0 80 mg/kg 80 mg/kg + lysine Gelofusine:

3 h p.i.

SPECT/CT of CA20948 rat tumour (111In-octreotate)

Reduction of renal retention by co-administration of Gelofusine/lysine

Different tracers in one animal

278 MBq

[177Lu-DOTA]octreotate

5 days after therapy

(injection radiopeptide)

50 MBq

[99mTc]DMSA

3h after injection

120 days after therapy

50 MBq

[111In-DTPA]octreotide

4h after injection

28 days after therapy

Longitudinal SPECT

111In-DTPA: Glomerular filtration (green)

99mTc-MAG3: Tubular extraction and secretion (brown)

Dual isotope dynamic SPECT/CT

Control PRRT PRRT + lysine 99mTc-MAG3

0 10 20 30 400

5

10

15

20Control

460 MBq177

Lu-tate

460 MBq177

Lu-tate + Lys

min.

%ID

Melis et al. JNM 2010

Challenges and Pitfalls

Peptide Receptor Imaging

• SPECT:

• - anesthesia, body temperature control

• - high ligand amount (partial) receptor saturation

• - specific activity (# MBq/nmol) should be high,

– but: radiochemical limitations!

2 g 10 g0

1

2

3

4

5 3.63% IA/g

2.24% IA/g

%IA

177L

u-t

ate

/g

The trade-off space - acquisition parameters: trade off between

acquisition time

resolution

signal to noise ratio

Peptide Receptor Imaging

• PET:

• - spatial resolution

Targeted vs metabolic imaging of prostate cancer model in mice.

4 VCaP-bearing mice:

• 68Ga-AMBA (bombesin analogue)

• 18F-choline

Arrows indicate tumour location

Schroeder RP et al. EJNMMl 2011

18F-FDG PET

Effect of anesthesia:

Toyoma et al. NMB, 2004 Fueger et al JNM 2006

18F-FDG PET

Effect of body temperature: cold animals compensate by activating brown fat

Courtesy HJ Li and H Herschman

Conscious without heating Unconscious with heating

18F-FDG PET

Effect of body temperature: same mouse imaged 2 days apart

without heating with heating

tumour

Variances in temperature could mask changes in 18F-FDG

uptake due to tumour growth or interventions.

18F-FDG PET

Effect of:

• Anesthesia

• Body temperature

• Fasting

To obtain accurate and consistent data from imaging studies:

- proper understanding of the biology

- animal preparation is very important

Dopamine w/ [99mTc] TRODAT Neuroscience

Uptake of [123I] IBF by D2 receptors

Stress [99mTc] MIBI Cardiovascular

[99mTc] MIBI

Renal Cell Carcinoma Oncology

[99mTc] Minigastrin

Mouse Human

*functional imaging

Animal versus human

Which anatomical imaging modalities can be combined with PET and SPECT?

• CT

• MRI

• Ultrasound

• Other functional imaging combinations include

• Fluorescence

• Bioluminescence

PET-MRI an emerging field clinically

Multimodal capabilities

SPECT-MRI

Optical – SPECT/PET – CT

SPECT scan of subchondral bone turnover

micro-CT MPH-SPECT MPH-SPECT/CT

•99m-Tc-MDP tracer

•Multi Pinhole SPECT

•Rat model, OA induced by MIA

SPECT and MRI – tumor vasculature and peptide uptake

• Targeted radiopeptides showed that the tumor did not have equal distribution

CA 20948 rat

pancreatic

tumor

H69 human

small cell lung

carcinoma

PC295 human

prostate tumor

Perfusion MRI

• After contrast injection multiple T1 images are acquired to measure the change in voxel signal intensity.

SPECT and MRI – tumor vasculature and peptide uptake

AUC60 SPECT

Overlay

SPECT-MRI Fusion

DMSA Fused with T1

DMSA Fused with T2

11C-PIB PET: dynamic scan data at 30–60 min after administration to detect

amyloid plaques in APP Tg mice at different ages.

Mouse model of Alzheimer's disease: PET-MRI

Neurosciences

Svedberg et al., NM&B 2012

Courtesy of Nikolaus et al. Clinic of Nuclear Medicine, Heinrich-Heine University, 40225 Düsseldorf,

Germany Central Laboratory for Electronics, Research Center Jülich, 52428 Jülich, Germany

Uptake and displacement of 123I-IBF in

striatum by injection of haloperidol

Injection of haloperidol

Time-activity curve in striatum

Kinetic brain imaging of dopamine D2 receptors (Parkinson’s disease, Huntington’s, drug abuse)

Neurosciences

Optical and SPECT tumor imaging

M van Oosterom J.Nuc Med 2014

Modality Role Sensitivity

potential

Spatial resolution Temporal

resolution

MRI anatomy & function low ~ 100 m ms

CT anatomy low ~ 20 -100 m s

PET Biology very high ~ 1-2 mm 10’s s

SPECT Biology high ~ 1mm min.

Optical

US

Biology

Anatomy/

delivery

very high

N/A

Mm (depth limited)

< mm

10’ s

ms

Comparison of modalities

Friday’s experiment

Longitudinal follow-up of tumors treated with

radionuclide therapy

Therapy response monitoring with SPECT-MRI

The main directions in molecular imaging are:

- Optical Imaging (OI)

- Computer Tomography (CT)

- Positron Emission Tomography (PET)

- Single Photon Emission Computed Tomography (SPECT)

- Magnetic Resonance Imaging (MRI)

- Raman Spectroscopy

- Ultrasound (US) technology

AMIE@erasmusmc.nl

www.erasmusmc.nl/amie