F-18 and Ga-68: Potentially «Deadly Poisons» for ... · Why does the world like PET? 2....

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29.09.2016 Slide 1© Dept. Medical Radiology

F-18 and Ga-68: Potentially «Deadly Poisons» for Conventional Nuclear Medicine ?

Gustav K. von Schulthess, MD, PhD, MD honAnass Johayem, PhD

Nuclear Medicine and RadiopharmacyUniversity Hospital Zurich, Switzerland

AcknowledgementsPhilipp A. Kaufmann; MD, Anass Johayem, PhD; Irene Burger, MD; Martin Huellner, MD;Erik Stromqvist, MS*

*GE Healthcare Uppsala, SE


Conflict of interest declaration

1. Consultant to GE Healthcare

2. Grant recipient Bayer, GE Healthcare, Guerbet, Lilly, Sirtexmostly in the function of:

3. Course Co-Director International Diagnostic Course Davos (IDKD)Swiss Non-Profit Organisation, providing world-wide organ basededucation in imaging in workshops www.idkd.org

- IDKD Rio de Janeiro, Brazil:, November 4-6, 2016- IDKD Davos, Switzerland: Musculoskeletal, March 26-30, 2017- IDKD Asia (Hong Kong and Beijing): Chest, Heart, Vessels,

Hong Kong, May 28-30, Beijing, June 4-6, 2017- IDKD Athens, Greece: Neuro, September 29-October 1, 2017

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Table of contents

1. Why does the world like PET?

2. USZ PET-Radiopharmacy

3. Examinations available in Nuclear Medicine and PET

4. Examinations available in PET only

5. Can PET-exams replace all NM exams?


Why does the world like (FDG-)PET(-CT)?

1. Spatial resolution down to ≈ 2 mm, axial FOV up to 25 cm

2. Electronic collimation (dual photon effect)

3. Attenuation correction- easy with CT (more difficult with MR)- potential emission only by TOF-PET

4. “Wonderful” tracers like FDG, not available in conventional Nuclear Medicine

5. Short half lives of PET radioisotopes- easy biomolecule label: F, C, N, O- minimize nuclear waste

=> Only problem: tracer logistics

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Table of contents


2. Presentation of USZ PET-Radiopharmacy

3. Tracers used in Nuclear Medicine and PET


5. Ga-68 logistics

6. Conclusions


USZ and PET Radiopharmacy

1. 12.1993 PET installed (now 3 PET/CT and 1 PET/MR)

2. 4. 1995 PET-Radiopharmacy productive (FDG, NH3, H2O)- PET-Trace based RPh production- business analysis: need to sell=> GMP lab from the outset

3. 2000 FDG PET reimbursed=> growth of PET market => USZ forcibly becomes tracer provider

4. Current: USZ provides 2/3 of PET tracers in SwitzerlandPopulation > 8 Mio = > 20’000 of 30’000 doses / year

5. 2015 2nd production facility opened

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PET examinations USZTotal PET: N = 5’800

these tracersuse Ga-68

*


USZ numbers

1. Currently > 5’800 PET examinations

2. Currently > 20’000 doses of PET-tracers / year produced- F-18-FDG- F-18-Choline- F-18-Tyrosine- F-18-Na-F- N-13-NH3- O-15-H2O- Ga-68 PSMA- Ga-68 DOTATATE- F-18-Flutemetamol- C-11-PIB- other research tracers

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Table of contents





5. Ga-68 logistics

6. Conclusions



Replacement of conventional Nuclear Medicine by PET

has started a decade ago

Ga-DOTA-peptides vs In-Octreotide (USZ 10 -> 150/year, partly reimbursed)

NH3 PET is clearly better than Nuc perfusion studies (reimbursed)

FE-Tyrosine use is increasing (reimbursed)

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T1 MRI + C FET PET & MRI

FET PETFDG PET

A

B

CBV DSC MRI

T1 MRI + C FET PETFDG PET

MRI vs FDG- vs FET-PET vs DCMRIan Law: Mol-Anat Imaging, G. v. Schulthess ed 2015


F-18 Ethyl Tyrosine (FET) Brain Tumor Imagingreplaces old brain scans for brain tumor imaging

1. F-18-FET and other Amino Acids like C-11-Methionine are best forevaluating malignancy of brain tumors

2. F-18-FET is easy to produce and is readily shipped

3. F-18-FET is not sensitive enough to evaluate malignant bodytumors

4. F-18-FET is accepted by the Swiss «FDA» and reimbursed forbrain tumors by the Swiss Health Authorities

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F-18-NaF-PET/CTdegenerative and metastatic changes

degenerativedisease

vertebral archmetastasis

vertebral bodymetastasis


F-18-NaF-PET/CT Bone ScanningReplaces bone scans with Tc-99m-MDP/DPD agents

1. F-18-NaF is a much better bone scanning agent than the Tc-99m labeled bone scanning agents

2. F-18-NaF is easy to produce and is readily shipped

3. Use of F-18-NaF-PET for bone mets limited, as specific FDG, F-Choline, Ga-DOTA-peptide and -PSMA-11 available

4. Use of F-18-NaF-PET for benign bone disease largely unexplored(literature survey)

5. F-18-NaF-PET approved by «Swiss FDA», but not reimbursed bythe Swiss Authorities (cost compared to bone scan)

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O-15 Water brain perfusion in Moya-Moya diseaseBaseline cerebral perfusion scan with Acetazolamide stress

0.6

0.00.6

0.0

ml/

mlT

iss/

min

ml/

mlT

iss/

min

0.07

0.0

ml/

mlT

iss/

min

Dia

mox

Bas

elin

eD

iffe

renc

e


O-15 Water PET Brain Perfusion ScanningReplaces brain perfusion scans

1. O-15-H2O PET is a better procedure than conventional NUC brain perfusion scans

2. O-15-H2O PET is quantitative

3. O-15-H2O PET needs a cyclotron in-house near the scanners

4. O-15-H2O PET can be produced according to a pharmacopea(in-house use only), but is not reimbursed by the Swiss HealthAuthorities

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PET myocardial perf. Imaging with NH3 or Rb


PET vs SPECT in myocardial perf. imagingN = 2’159, Merhige E. et al, JNMMI 2007

Use of perfusion (Rb) PET vs myocardial perfusion SPECTCoronary Angiography procedures reduced from 30 to 15%Cost reduced by 20%

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NH3 or Rb Myocardial Perfusion ScanningReplaces myocardial perfusion scans with Mibi/Myoview

1. N-13-NH3 and Rb-82 are much better myocardial perfusion agentsthanTc-99m-MIBI/Myoview

2. N-13-NH3 requires an in-house cyclotronRb-82 is generator produced, unfortunately very expensive!

3. N-13-NH3 requires production according to pharmacopea(in-house use only),Rb-82 needs an approved generator

4. Procedure reimbursed by the Swiss Authorities

=> explicit wish that there is a shift from conventional NUC to PET


PET vs. SPECT in myocardial perf. imagingFlurpiridaz, a new F-18 based PET tracer

Flurpiridaz

F-18 based alternative toNH3 and Rb

Advantage:centralized production

Disadvantage:half life of 109 min withclearance characteristics like with MPI SPECT tracers

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In-11-Octreo-SPECT vs Ga-68 DOTATOC

PE

TS

PE

CT

Buchmann et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. EJNM 2007

Dramaticdifference


Ga-68-DOTA-peptidesReplace tumor scanning by In-111-Octreotide

1. Ga-68-DOTA-peptides are much better tumor scanning agentsthan In-111-Octreotide

2. In ZRH usage from 15 yearly scans to >150 yearly scans

3. Ga-68 logistics?

4. Ga-68 based «orphan» tracer (< 100 scans needed per 1 Mio/y)

5. Ga-68-DOTA-peptides are partly reimbursed in Switzerland

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PET/CT2 min/bed

PET/MR1 min/bed

PET/MR3 min/bed

MIP PET/CT vs PET/MRFDG is THE PET tracer

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FDG-PET for inflammatory processes

Spondylo-discitis

Synovitis


F-18-FDGTumor (no replacement) and inflammation imaging

1. F-18-FDG is THE PET tracer which has made PET big

2. While FDG is well established in tumor imaging, its use in inflammation imaging is lagging behind

3. F-18-FDG is easy to produce and is readily shipped

4. F-18-FDG is accepted by the Swiss «FDA» and reimbursed forvirtually all tumors by the Swiss Health Authorities

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FCH-PET/CT

FCH-PET/CT

5.6

6.6

early phase

late phase

FCH-PET/CT

FCH-PET/CT

4.8

5.5

early phase

late phase

FCH-PET/CT

FCH-PET/CT

5.2

5.9

early phase

late phase

Initial tumor stage: pT3a cN0 cM0, Gleason 6

Dual phase Choline-PET/CTrecurrence (PSA 13,1)


5.1

8.5

late phase

early phase

FCH-PET/CT

FCH-PET/CT

late phase

FCH-PET MIP

early phase

FCH-PET MIP

Dual phase Choline-PET/CTrecurrence (PSA 0.3)

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F-18-CholineProstate cancer imaging

1. Choline PET tracers second most widely used PET tracers in Switzerland

2. Choline PET tracers are easily produced and shipped

3. Estimated market potential 10-20% of FDG market

4. Sensitivity gap: > 50% scans + for PSA > 2.0 ng/ml

5. Approved by «Swiss FDA» and reimbursed by Swiss HealthAuthorities


Amyloid Scanning: C-11 PIBBiogen and Neuroimmune/Univ. Zurich

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Amyloid Scanning: C-11 PIB - Alzheimer?Nature Abstract


Amyloid tracersDementia imaging

1. Not yet widely used due to lack of clinical impact

2. The 3 patented F-18 based compounds are easily produced bysynthesis modules and shipped

3. Estimated market potential huge, if amyloid removal trialssuccessful (we will know in 5 years or so)

4. Amyvid approved by «Swiss FDA»

5. Not reimbursed by Swiss Health Authorities

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NUC examinations USZTotal NUC: N = 4’850 (< PET N = 5’800)


I-124 or thyroid carcinomathyroid remnants in pat prior to radioiodine Rx

A B C D

Bockisch et al: Molecular-Anatomic Imaging, G. von Schulthess ed. 3rd edition 2015

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I-124 IodineThyroid (cancer) imaging

1. Very useful in thyroid disease

2. Not widely available, but due to 4.2 days T ½ shippable

3. Relatively expensive compared to I-123 and particularly I-131


F-Choline PET/MR – Parathyroid disease61 year old female. Primary hyperparathyroidism

Orevi M et al. Localization of parathyroid adenoma by (1)(1)C-choline PET/CT: preliminary results. Clin Nucl Med 2014;39:1033-1038.

Lezaic L et al. (1)(8)F-FluorocholinePET/CT for localization of hyperfunctioningparathyroid tissue in primary hyperparathyroidism: a pilot study. Eur J Nucl Med Mol Imaging 2014;41:2083-2089.

PET/MR

61 yo female. Primary hyperparathyroidism.

* Disclaimer: Off-label use

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Huellner MW et al. Visualization of Parathyroid Hyperplasia using 18F-Fluorocholine-PET/MR in a Patient withSecondary Hyperparathyroidism. Clin NuclMed 2015 Oct 12 [ahead of print].

PET/MR

35 yo male. Secondary hyperparathyroidism.

* Disclaimer: Off-label use

F-Choline PET/MR – Parathyroid disease35 year old male with secondary hyperparathyroidism


Table of contents





5. Ga-68 logistics

6. Conclusions

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Useful isotopes in PET imagingPositron range varies from 0.6 – 6 mm

43Sc 476

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Table of contents





5. Ga-68 logistics

6. Conclusions


Ga-68: Analogue of Tc-99m for PETTc-99m chemistry can be translated into Ga-68 chemistry

1. Ga-68 is a metal ion

2. Ga-68 can be bound via chelator=> Chelator-biomolecule complex synthesized at leasure. Ga-68 “snapped on”=> Advantage when labeling peptides and proteins

3. Ga-68 is suitable for kit production

4. Ga-68 can be produced by a generator

5. Chelator-based tracers = useful theragnostic compounds

Ga-68 seems the perfect PET equivalent to Tc-99m

Some issues have to be looked at though!

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Issues warranting discussion with Ga-68

1. 1/2-life = 68 min: distribution or decentral productionto be discussed

2. Positron range is around 5 times larger than for F-18=> somewhat inferior spatial resolution compared to F-18

3. Generator yield: 2 – 3 doses onlyneed high volume application to change this

4. ½ life of 270 days=> creates some waste disposial/activity recovery issues


Distribution radius F-18 / Ga-68 compoundsF-18 =110 min / Ga-68 = 70 min. radius for delivery

2h 20’

2h 10’

1h 20’

2h 15’

2h 50’

1h 30’

40’

40’1h 10’60’

1h 20’

40’

F-18 will distribute throughout Switzerland in 2 half lives (8 Mio) Ga-68 will distribute to many Swiss sites in 2 half lives (5 Mio)

MilanoLyon

Munich

Strassburg/Karlsruhe2 T1/2 F-18 = 10 Mio2 T1/2 Ga-68 = 6 Mio

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Problems with current Ga-68 productionThe «batch cost» vs. «dose price» gap

1. Most costs reside with batch production - personnel- chemicals / pharmaceuticals / equipment- sterility / toxicity tests- regulatory affairs

2. Revenue is mostly dose based, except for- portioning- transport of substance

=> Dose production cost ~ batch cost / # doses


The «batch cost» vs. «dose price» gap

General batch cost PET tracers2‘000 – 6‘000 CHF / US$ / €

# doses dose priceUS$ / € / CHF

1 4‘0002 2‘0004 1‘0008 500

16 25032 125

without transportation cost!

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Production yield F-18 based compoundsHalf life F-18 = 110 minutes

Radiotracer GBq mCi doses @ T1/2

FDG 250 6700 60-80

F-Choline 125 3380 30-40

F-Ethyltyrosine 125 3380 30-40

Can we achieve this also with Ga-68 compounds?

Can we offset any investment into this?


Ga-68-PSMA-11 in recurrent PcaGa-68-PSMA-11 is a “Killer” Application

A BI

II

III

I

II

III

F-Choline Ga-PSMA-11

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Ga-68-PSMA-11 PET/MR for restaging

PSMA AxPSMA MIP T2 axial

DWI axial DCE axial

T2 & PSMA Ax

75 y.o. man with PCA after prostatectomy 2005: 2015-2016: PSA 0.2 -> 0.5 ng/ml


Ga-68-PSMA-11 as a “Killer” Application?

Recurrent Prostate Cancer

Urologist worries when PSA rises above 0.2 ng/mL

Choline tracers detect > 50% of recurrences above 2.0 ng/mL

Ga-68 PSMA-11 > 50% of recurrences above 0.2-0.5 ng/mL

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What are “Killer” Applications?

A technology can be introduced successfully only, if there is a clinical “blockbuster” application

1. CT started with brain and body imaging as a “killer app”

2. MR started with brain as “killer app”

3. PET started with FDG and oncology as “killer app”and PET/CT followed suit

4. New tracers: Choline satisfying an important clinical needGa-68-PSMA-11: estimated use 10-20% of FDG


Production yield Ga-68 based compoundsHalf life F-18 = 68 minutes

Tracer origin GBq mCi doses doses at site @ T1/2

- generator based 1 25 2-3 1- liquid target 2 50 4-6 2-3- solid target 100 2’700 20-40 10-20

This will solve the Ga-68 generator issues- low yield / radioactive waste disposal and recovery

Only high yield Ga-68 production will allow distribution of labeled tracer or Ga-68-Chloride to distant sites

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Issues with cyclotron Ga-68

1. Solid targetry more complex than liquid target technology- get target into beam and out again by mechanical gimmick- dissolve solid target and purify- synthesize tracer

2. Radiolysis ok at 2 doses, how about 20 doses?


Ga-68 can be used in kit labelingready to use applications under development

Radiotracer

1. DOTA-peptides (NOC, TOC, TATE) (FDA-approved)

2. PSMA (available for research)

3. Pentixafor (CXCR4 receptor ligand)

4. Others (no extensive literature review done)

Distribute Ga-68 as ionic solution for kit labeling

Depending on Ga-68 labeling infrastructure needed, some sites may want Ga-68 ion, others Ga-68 tracer

Kit technology not accessible to F-18

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Further optimization andcharacterization of ligands

o ‐emitters, low‐energy ß‐emitters o Fluorescent CXCR4 ligandso Hybrid Probeso CXCR7 ligands

Mantle cell lymphoma Multiple Myeloma

[68Ga]Pentixafor /[177Lu]Pentixather[68Ga]Pentixafor PET in lymphoproliferative diseases

24.8 ± 2.5

Peptide IC50 [nM]

Ga‐Pentixafor

Lu‐Pentixather

Y‐Pentixather

Bi‐Pentixather

14.6 ± 1.0

20.4 ± 0.3

4.4 ± 1.3

CXCR4 affinity

AlF‐NOTA‐Pentixather

Cu‐NOTA‐Pentixather

17.9 ± 0.3

14.9 ± 2.1Wester HJ, Schottelius M et al


Development CXCR4 PET tracer Pentixafor

Daudi

SU-DHL-8

PET-CT (xenografts)Pentixafor PET (patient)

Kidney

Patient imaging:10/14 MM positive7/7 aggr. NHL positiveWester, Keller et al. Theranostics 2015

Gourni, Demmer et al. J Nucl Med 2011

68Ga-Pentixafor(~50pmol)

+ Plerixafor (~100nmol)

68Ga-Pentixafor(~50pmol)

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Ga-68 EDTA PET/CT Dynamic Renal Imaging

Hofman MS and Hicks RJ. Seminars in Nuclear Medicine

2016; 46:448-461


PET vs. SPECT V/Q

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Sentinel Node Imaging with Ga-68 nanocoll. PET/CTCourtesy Rodney Hicks, Melburne, Au



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Summary: Ga-68 pipeline for distribution

1. We have all the tools to replace conventional NM with PETGa-68 can be produced in Curie quantities from solid targets

2. Ga-68 is better for peptide and protein labelling than F-18

3. Ga-68 is a better partner in a theranostic pair than F-18

4. Ga-68 distribution radius is 68/110 = 62% of that of F-18e. g. can also be distributed regionally

5. Ga-68 can be used to label kits, which has many advantages

F-18 and Ga-68: Potentially «Deadly Poisons» for ... · Why does the world like PET? 2....

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