Radiopharmaceuticals used for diagnosis and treatment of neuroendocrine tumours

Head of Radiopharmaceutical Research Department of Nuclear Medicine, PET & Clinical Ultrasound, Westmead Hospital & The Children’s Hospital at Westmead.

SYDNEY, AUSTRALIA.

Vijay Kumar MSc (Med), PhD

Clinical Professor

Sydney Medical School, Sydney University Discipline of Medical Imaging &

Discipline of Paediatrics and Child Health.

Second international conference on Clinical PET and Molecular Nuclear Medicine (IPET 2015)

5-9th Oct 2015, IAEA – Vienna. Sydney University Westmead Hospital

Historic beginning of NET Imaging: The radiopharmaceutical that was first used in patients to study human NET is 123I-Tyr3-octreotide [Krenning et al Lancet 1989; 1:242]. But, 123I labelled agents had several limitations: high costs difficult labelling procedure accumulation of the radiopharmaceutical in the bowel etc.

Therefore, 111In-DTPA-D-Phe1-octreotide (111In-pentetreotide) was developed by the Rotterdam group [published 1000 Patients study EJNM 1993;20:716]. This tracer became the first radio-receptor agent commercially available as OctreoScan, by Mallinckrodt Medical, St. Louis, MO, USA. It was approved in 1994 by the US Food and Drug Administration as an imaging agent for somatostatin receptor-positive NET.

Introduction of DOTA as a chelator (1990+): On the diagnostic side, 111In-DOTA-D-Phe1-Tyr3-octreotide shows similar biodistribution as111In-DTPA-D-Phe1-octreotide Three other tracers were developed:

111In-DOTANOC(1-NaI3-octreotide)

111In-DOTANOC-ATE (1-NaI3-Thr8-octreotide) and

111In-DOTABOC-ATE, (Bz-Thi3-Thr8-octreotide), The replacement of octreotide with octreotate has eventually shown a decrease of lipophilicity, boosting the affinity for the sstr2.

99mTc-labelled somatostatin analogues have been developed, namely the 99mTc-N- α-(6 hydrazinonicotinoyl)-octreotide (99mTc-EDDA/HYNIC OCT) [Maecke HR et al EJNM 2000;27:628; Decristoforo C et al J Nucl Med. 2000] At that time, propagation of the tracer was hampered by proprietary rights for the peptide. For this reason it has remained a tracer for in-house use. Interestingly it is currently being offered as a routine product by POLATOM (Warsaw, Poland). Besides imaging of NET it has been used in the study of thyroid-associated orbitopathy

Somatostatin receptor expressing tumors

Somatostatin receptor octreotide (SMS 201-995) human SRIF-receptor subtypes hSSTR1 > 1000 nmol / L hSSTR2 0.32 nmol / L hSSTR3 31.6 nmol / L hSSTR4 > 1000 nmol / L hSSTR5 7.3 nmol / L

N-terminus

C-terminus

G protein

Ligand

response

plasmamembrane

hsstr2 protein

A high density of somatostatin receptors is found in neuroendocrine tumors: such as pituitary adenoma, pancreatic islet cell tumor, carcinoid, Neuroblastoma, pheochromocytoma, paraganglioma, medullary thyroid cancer, small cell lung carcinoma (Reubi, 1997).

Further improvements in the development of radioreceptor RP were based on DOTA, a more universal chelator for metal ions, BFC (eg. DOTA) can be used to chelate diagnostic isotopes such as 68Ga, or therapeutic radionuclides eg. 177Lu & 90Y. The BFC is the under-pinning strength behind the THERNOSTICS

Bifunctional Chelator (BFC)

sstr

68Ga,177Lu, 90Y

BFC – DOTA, NOTA, NODAGA etc

sst

Acyclic Chelators:

Bifunctional chelators (macrocyclic):

Chem Med Chem 2013, 8, 95 – 103 96

Most Frequently used Bifunctional chelators:

(D)Phe - Cys - Tyr - (D)Trp

Thr(ol) - Cys - Thr - Lys

68Ga

DOTA

Eur J Nucl Med Mol Imaging (2007) 34:982–993 P. Antunes &M. Ginj & H. Zhang & B. Waser R. P. Baum & J. C. Reubi & H. Maecke

Somatostatin Analogs

Eur J Nucl Med Mol Imaging (2007) 34:982–993

P. Antunes &M. Ginj & H. Zhang & B. Waser R. P. Baum & J. C. Reubi & H. Maecke

generator

mother daughter

T½ T½ b+branch (%) Eb+ (MeV) main use

82Sr / 82Rb 25.6 d 1.27 min 95.0 1.41 perf. 140Nd / 140Pr 3.37 d 3.39 min 51.0 0.544 perf.

118Te / 118Sb 6.00 d 3.6 min 74.0 0.882 perf.

122Xe / 122I 20.1 h 3.6 min 77.0 1.09 (label.) 128Ba / 128Cs 2.43 d 3.62 min 69.0 0.869 perf.

134Ce / 134La 3.16 d 6.4 min 63.0 0.756 perf.

62Zn / 62Cu 9.26 h 9.74 min 97.0 1.28 label.; perf.

52Fe / 52mMn 8.28 d 21.1 min 97.0 1.13 perf. 68Ge / 68Ga 270.8 d 68 min 89.0 0.74 perf. →label.

44Ti / 44Sc 47.3 yrs 3.927 h 94.0 0.597 label. 72Se / 72As 8.4 d 1.083 d 88.0 1.02 label.

PET generator systems for life sciences

F Rösch, FF (Russ) Knapp. Radionuclide Generators. in A Vértes, S Nagy, Z Klencsár, F Rösch (eds.), Handbook of Nuclear Chemistry – Vol. 4, pp 81-118, 2003, Kluwer, The Netherlands

•1960 GLEASON GI: A positron cow. Int J Appl Radiat Isot 8:90-94.

•1961 GREENE MW, TUCKER WD: An improved gallium-68 cow. mt J Appl Radiat Isot 12:62-63 •1964 YANO J, ANGER HO: A gallium-68 positron cow for medical use. J Nucl Med 5:484;487. •1975 MALYSHEV KV, SMIRNOV VV: A generator of gallium-68 based on zirconium hydroxide. Radiokhimiya 27:137-140

•1978 EHRHARDT GJ, WELCH M: A new Germanium-68/Gallium-68 generator. J Nucl Med I9:925-929. •1979 NEIRINCKX RD. Davis MA: Development of a generator for ionic gallium-68. J Nucl Med 20:681-682. •1979 YVERT JP, MAZIERE B, VERHAS M, et al: Simple, fast prepa ration of gallium-68-labelled human serum albumin microspheres. Eur J Nucl Med 4:95-99.

• In 1960, the first 68Ge/68Ga Radionuclide Generator was described by GLEASON GI: A positron cow. Int J Appl Radiat Isot 8:90-94. • In 1964 Modified by YANO J, ANGER HO: A gallium-68 positron cow for medical use. J Nucl Med 5:484;487. 0.005M EDTA 68Ga- EDTA

• The generator design and product may not be up to the standard, but it served the medical needs, particularly for brain imaging at that time period.

Al2O3

• A new type of generators became commercially available in the early 2000, based on generator elution with dilute HCl, which provided “Cationic 68Ga” instead of inert “68Ga complexes”. Razbash et al 2005; Proc of 5th Int. conf on Isotopes, 5ICI, Brussels. • Post-processing of Ga-68 generator elute was described in 2004 • By Zhernosekov, Filosofov, Baum….Roesch et al . J Nucl Med 48:1741.

“Cationic 68Ga” instead of inert “68Ga complexes”

• The concept of “Cationic 68Ga” is the beginning of “Renaissance” of 68Ga-Generators and 68Ga-Radiopharmaceuticals

• But more importantly the great potential of the 68Ge/68Ga Generator was unleashed. • Utilization of 68Ga-Octreotides became extensive towards clinical

acceptance of this agent for NET imaging. • Several commercially available generators and automated

synthesisers have revolutionised their application. • The inherent diagnostic potential has led to treatment planning and THERANOSTICS became increasingly acceptable & extensively used

„Heidelberg“ Obninsk EZAG-IGG100 iThemba

Elution 5.5N HCl 0.05N HCl 0.1N HCl 0.1N HCl 0.6-1N HCl 1NHCl

and....?

Titanium-dioxide Tin-dioxide

ITG

Organic Matrix

IPL

68Ge/68Ga Generators – currently in use

Thank you

Insert GMS generator

disseminated bone metastases of primary neuroendocrine tumors

Comparison of 18F-FDG, 111In-OctreoScan and 68Ga-DOTATOC [Patient: male, *1939, neuroendocrine tumor with unknown primary, multiple liver and bone metastases]

Klinik für Nuklearmedizin und PET-Center, Klinikum Stuttgart, Stuttgart; Institut für Kernchemie, Johannes Gutenberg-Universität, Mainz

FDG 111In-Octreoscan 68Ga-DOTATOC

Damian Wild1, Helmut R. Macke1, Beatrice Waser2, Jean Claude Reubi2, Mihaela Ginj1, Helmut Rasch1, Jan Mu¨ller-Brand1, Michael Hofmann3

Eur J Nucl Med Mol Imaging (2005) :724

68Ga-DOTANOC: a first compound for PET imaging with high affinity for somatostatin receptor subtypes 2 and 5

Image of the month, EJNM 2005

Multiple vertebral paraganglioma

68Ga-DOTA NOC

SNM Image of the Year 2008

68Ga-DOTA NOC

68Ga-labelled peptides for diagnosis of GEP- NET V. Ambrosini & D. Campana & P. Tomassetti & S. Fanti

Westmead Hospital, Sydney

68Ga-DOTa-TaTE NOrmal BiODisTriBuTiON

Westmead Hospital, Sydney

68Ga-DOTa-TaTE BrONchial ca

Westmead Hospital, Sydney

68Ga-DOTa-TaTE

NEurOfiBrOmaTOsis - 2 Nf2

Westmead Hospital, Sydney

68Ga-DOTa-TaTE iNsuliNOma PaNcrEaTic

Westmead Hospital, Sydney

68Ga-DOTa-TaTE PaNcrEaTic ca, livEr mETs

Westmead Hospital, Sydney

68Ga-DOTa-TaTE ParOTiD ca

Westmead Hospital, Sydney

68Ga-DOTa-TaTE mTc – mEDullary Thy ca

DOTA-TOC

DOTA-TATE

DOTA-TOC

DOTA-TATE

68Ga sst analogs for imaging:

•NET √ •Neural Crest Tumors •GEP Tumors

18F –FDOPA 123I– MIBG 68Ga- Antagonists 18F - FDG

18F-DOPA (Fluorodihydroxyphenylalanine) for Imaging NET 18F-DOPA - is superior in diagnostic performance in a limited number of precise NET types: • Medullary Thyroid Cancer • Catecholamine-producing tumours with low

aggressiveness • Well-differentiated carcinoid tumours of the mid-gut • Congenital hyper-insulinism

• Large Multicentre study results indicate patient-based sensitivity:

• Medullary Thyroid Cancer • Sensitivity was 70% [95% confidence interval 62.1 -77.6] for FDOPA • Sensitivity was 44% [95% confidence interval 35.0 -53.1] for FDG • Pheochromacytoma / Paraganglioma: • Sensitivity was 94% [95% confidence interval 91.4- 97.1] for FDOPA • Sensitivity was 69% [95% confidence interval 60.0 -77.1] for FDG

• Well-differentiated carcinoid tumours of the mid-gut • Sensitivity was 89% [95% confidence interval 80.4- 95.1] for FDOPA

EJNMMI (2013); 40:943-966

Adrenal Tumour & Aggressive Pheochromocytoma

18F-DOPA

Adrenal tumour

18F-DOPA 68Ga-DOTA-NOC

18F-DOPA 68Ga-DOTA-TATE

123I- MIBG

VS

68Ga-DOTA-TATE

123I-MIBG 68Ga-DOTA-TATE

SRS SRS MIBG MIBG

7

28

AGONISTS

VS

ANTAGONISTS

Wild D et al., J Nucl Med 2011;52:1412-1417

Wild D et al., J Nucl Med 2011;52:1412-1417

111In-Octreoscan® scintigraphy 24 h p.i.

111In-DOTA-BASS scintigraphy 24 h p.i.

111In-DOTA-JR11 scintigraphy 24 h p.i.

Agonist Antagonist Antagonist

A – Before Treatment B - 3mo after Treatment (15GBq) of 177Lu-DOTA-JR11 C - Before Treatment D - 12mo follow-up scan

68Ga-DOTA-TATE imaging

18F - FDG

Tumor Vs

Inflammation

68Ga-DOTA-TATE

18F-FDG

A 62-year-old woman with increased calcitonin and CEA levels after surgery for MTC: a 18F-FDG PET/CT is negative. b & c = 18F-DOPA PET/CT (b) and 68Ga-somatostatin analogue PET/CT (c) show an area of increased uptake in a right retropharyngeal lymph node. FNAB confirmed the presence of MTC recurrence.

Fanti et al Eur J Nucl Med Mol Imaging (6-1-2012)

18F-FDG 18F-DOPA 68Ga- sst analogue

An 86-year-old woman with increased calcitonin and CEA levels after surgery for MTC. a–c 18F-FDG PET/CT shows multiple areas of abnormal uptake in the liver and in the cervical and mediastinal lymph nodes. d–f 18F-DOPA PET/CT shows increased uptake only in the cervical and mediastinal lymph nodes. g–i In contrast, 68Ga-somatostatin analogue PET/CT shows only weak uptake in the cervical and mediastinal lymph nodes

18F-FDG 18F-DOPA 68Ga- DOTATOC

Eur J Nucl Med Mol Imaging (6-1-2012) DOI 10.1007/s00259-011-2031-6

Management

Peter MacCallum Hosp Melbourne

Therapy

&

Therapy Monitoring

? Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals P Antunes, M Ginj, H Zhang, B Waser, RP Baum, JC Reubi, H Maecke, Eur J Nucl Med Mol Imaging (2007) 34:982–993

Me(III) based radiopharmaceuticals Gd(III) MRI, In(III) SPECT, Y(III) ERT, Ga(III) PET

Ga(III) Yes ! for Ga(III) vs. In(III) and Y(III)

0

5

10

15

20

25

30

35

1 h 4h 24h 48h

% ID

/gIn-111-OctreoScanIn-111-DOTATOCY-90-DOTATOCGa-67-DOTATOC

Comparison of sequential planar 177Lu-DOTA-TATE dosimetry scans with 68Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy

A. Sainz-Esteban & V. Prasad & C. Schuchardt & C. Zachert & J. Carril & R. P. Baum

A 64-year-old woman with NET diagnosed in 2001 (liver lesions identified at routine abdominal ultrasound were interpreted as benign). The patient underwent hysterectomy and ovariectomy and metastases were found in both ovaries as well as in lymph nodes resected in the lumbar region. OctreoScan™ showed positive liver lesions, but no primary tumor. Octreotide therapy (Sandostatin LAR™ 20mg) was started, but progressive disease occurred in 2007. (A) Gallium-68-DOTATOC imaging at that time showed an intense SSTR-positive liver lesion in S8 (SUVmax = 33) and another, small lesion in S2 (SUVmax = 6.2), long solid and dashed arrows, respectively, on the maximum intensity projection image. The primary tumor was detected in the presacral region (SUVmax = 70.1) (short arrow). Left axial images (center column) are obtained at the level of the large liver lesion; right axial images (right Banerjee and Pomper Page 28 Appl Radiat Isot. Author manuscript; available in PMC 2014 June 01. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript column) are obtained at the level of the presacral tumor. (B) Peptide receptor radionuclide therapy (PRRT) was started in July 2007 (two cycles using a total of 8 GBq 90YDOTATATE) and follow-up PET/CT in January, 2009 showed complete remission of the liver metastases and partial response of the presacral lesion. To date, the patient is alive and doing well (nearly five years after PRRT) (Courtesy: Dr Richard P. Baum).

Pre-therapy Post-therapy (2 cycles of 9.0 GBq 90Y)

Comparison of sequential planar 177Lu-DOTA-TATE dosimetry scans with 68Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy A. Sainz-Esteban & V. Prasad & C. Schuchardt & C. Zachert & J. Carril & R. P. Baum

177Lu-DOTA-TATE 68Ga-DOTA-TATE

Concordant lesions

New Radiotheranostic Concepts based on Bisphosphonates

for the Treatment of Bone Metastases

PO3H2

PO3H2

R1

R2

N

N N

N

OH

O

HO

O

O

HO

O

OH

+

Combination: macrocyclic DOTA with bisphosphonate moiety

R1: H, OH R2: Alkyl, H2N-Alkyl, OP(OH)-Alkyl

High thermodynamic + kinetic stability with several radionuclides! Diagnosis and therapy in one and the same compound!

New concept

PET-Diagnosis

DOTA-bisphosphonates: theranostic tools (2010)

Endoradio- Therapy

Theranostics:

[68Ga]BPAMD Human Studies:

Lu-177 BPAMD post-therapy planar images (posterior view) in a patient of metastatic prostate cancer at 5 time intervals for dosimetry, showing high uptake in skeletal metastases with high contrast and long effective half life (retention), and rapid renal clearance.

Lu-177 BPAMD therapy was performed in patients with carcinoma of the prostate and skeletal metastases. No adverse effect in any one patient. The activity per cycle ranged from 3.5-6.4 GBq

The mean absorbed doses were calculated as follows: - skeletal mets: 2.4 -225 mGy/MBq. whole body: 0.03-0.14 mGy/MBq, kidneys: 0.11-0.65 mGy/MBq; red marrow: 0.04-0.1 mGy/MBq.

The clearance of Lu-177 BPAMD from whole body and normal organs as well as from the blood is very fast. On the contrary, skeletal metastases demonstrated a very long residence time (T1/2= 6.7days) of the tracer resulting in a high radiation dose. Therefore, Lu-177 BPAMD has excellent dosimetric characteristics for the treatment of skeletal metastases and a very low toxicity potential.