Ga radiopharmaceuticals: Current status and future radiopharmaceuticals: Current status and future ....

68Ga radiopharmaceuticals: Current status and future

VIENNA | IAEA – IPEN | 07x15

Frank Roesch Institute of Nuclear Chemistry

Johannes Gutenberg University Mainz

Germany

GENERATORS

CHELATORS

NEW CHEMISTRY NEW TRACERS

COMMERCIAL KITS

PET/CT FOR MAIN INDICATIONS

THERANOSTICS

GENERATORS

68Ga β+ 1.9 67.7 m

68Zn 27.9 % 6.2 b

68Ge ε

270.8 d

The PET 68Ge/68Ga generator Half-lives of parent and daughter, shelf-life,

Daughter lution efficacy, parent breakthrough

Secular equilibrium

1 day = 3 elutions 1 week = 15 elutions 40 weeks ( 1 x t½ of 68Ge) = 600 elutions á 3 patients = 1800 patients per generator

Half-life perfectly meeting clinical needs

0.6 N HCl 0.05 N HCl

0.1 N HCl

SnO

2

TiO

2

organic resins inorganic resins

Schumacher et al. 1981 Malyshev, Smirnov 1975 and many others

Loc´h et al. 1980

Roesch F, Riss PJ The renaissance of the ⁶⁸Ge/⁶⁸Ga radionuclide generator initiates new developments in ⁶⁸Ga radiopharmaceutical chemistry. Curr Top Med Chem (2010) 10(16):1633-68

The PET 68Ge/68Ga generator 68Ga-aqua cation elution chemistry

anod

e (+

)

cato

de (-

) 68Ga3+

ELECTROPHORESIS 0.1 HCl paper strip

The PET 68Ge/68Ga generator 68Ga-eluate purity / 68Ge breakthrough

I. Develop generators of sufficiently low breakthrough II. Register those generators for human use III. Define legal definitions for 68Ge levels

✔ ✔

✔

PA/PH/Exp. 14/T (08) 21 COM GROUP 14 (RADIOACTIVE COMPOUNDS / COMPOSES RADIOACTIFS)

Gallium chloride (68Ga) solution for radiolabelling Monograph N°: 2464

The radionuclide gallium-68 is obtained by elution of a 68Ge/68Ga generator using dilute hydrochloric acid. To ensure a sufficiently low level of the parent radionuclide germanium-68, the gallium-68 can either be adsorbed in the form of [GaCl4]− on an anion exchange column followed by elution from the column in the form of Ga3+ cations with water or diluted HCl, or be adsorbed in the form of trivalent gallium on a cation exchange column followed by elution with an acetone/hydrochloric acid mixture.

monographs of the European Pharmacopoeia (Ph. Eur.)

… B. Germanium-68 and gamma-ray-emitting impurities. Limit: the total radioactivity due to germanium-68 and gamma-ray emitting impurities is not more than 0.001 per cent.

The PET 68Ge/68Ga generator 68Ga-eluate purity / 68Ge breakthrough recommendations

company type Column

material

HCl

(N)

68Ga elution yield

(%)

68Ge breakthrough

(%)

EZAG, Berlin,

Germany

Obninska TiO2 0.1 initial

long term

≈75

60b

initial

long term

0.005

---e

IGG100 TiO2 0.1 initial

long term

>65

>65b

initial

long term

0.001

---e

iThemba LABS,

South Africa

SnO2 0.6 initial

long term

>100f

75c

initial

long term

<0.01f,g

n/ai

ITG Garching, Germany,

ITG iQS® Ga-68

Fluidic Labeling Module

Silica

basedh

0.05 initial

long term

>80

>80d

initial

long term

<0.005e

n/a

a Provided by Cyclotron Co. Ltd., Obninsk, Russia b After 200 elutions / c after 300 days / d throughout shelf-life of 4-6 months / e after 300 days or 1 year d Generators are delivered with a nominal activity of 68Ga eluted initially f Expressed as ratio of radioactivities of 68Ge/68Ga in the eluate g Values true for daily elutions only [22] h 3,4,5-trihydroxy-benzoate i No information available

Performances of commercial 68Ge/68Ga generators Values are taken form official product bulletins in the case of EZAG and ITG. For iThemba generators, >100% initial 68Ga yield are achieved by selling generators of higher nominal 68Ge load.


monographs of the European Pharmacopoeia (Ph. Eur.)

… B. Germanium-68 and gamma-ray-emitting impurities. Limit: the total radioactivity due to germanium-68 and gamma-ray emitting impurities is not more than 0.001 per cent.

To ensure a sufficiently low level of the parent radionuclide germanium-68, the gallium-68 can either be adsorbed in the form of [GaCl4]− on an anion exchange column followed by elution from the column in the form of Ga3+ cations with water or diluted HCl, or be adsorbed in the form of trivalent gallium on a cation exchange column followed by elution with an acetone/hydrochloric acid mixture.


I. Develop generators of sufficiently low breakthrough II. Register those generators for human use III. Define legal definitions for 68Ge levels … IV. and suggest post-processing methods to achieve it

Was

te

1 2

CATION -EX

Gen

erat

or

Ga-

68

Cation exchange-based Mainz

Cation exchange-based post-processing technologies generator eluate (e.g. 10 ml of 0.1 M HCl) transferred directly and online to a cation exchange column: 1. 68Ga adsorbed quantitatively online 2. Chemical impurities such as Fe(III), Zn(II), Ti(IV) eluted from cation exchange column into waste 3. Additional washing step 4. Transfer of 97±2% 68Ga @ + 4 min into final (labelling) vial chemically pure 5. 68Ge content / breakthrough: initially >10-3 % finally <10-7 % 6. low volume and low pH: 400 µl 0.05 N HCl / acetone further isolation of metalic impurities = high labelling yields = high specific activities eluted directly into labelling vial, containing amounts of precursor, e.g. 10-20 µg (7-14 nmole) DOTATOC, and an appropriate volume of water, without (or with) using buffer systems (5 ml water + 0.4 ml N2 = pH 2.3) >95% labelling at 10 min > 450 MBq / nmol DOTATOC ca. 65% yield referred to initially eluted 68Ga

Zhernosekov KP, Filosofov DV, Baum RP, Aschoff P, Bihl H, Razbash AA, Jahn M, Jennewein M, Rösch F, Processing of generator-produced 68Ga for medical application. J Nucl Med 2007; 48: 1741

Was

te

1 2

CATION -EX

Gen

erat

or

Ga-

68

Cation exchange-based Mainz

Cation exchange-based post-processing technologies generator eluate (e.g. 10 ml of 0.1 M HCl) transferred directly and online to a cation exchange column: 1. 68Ga adsorbed quantitatively online 2. Chemical impurities such as Fe(III), Zn(II), Ti(IV) eluted from cation exchange column into waste 3. Additional washing step 4. Transfer of 97±2% 68Ga @ + 4 min into final (labelling) vial chemically pure 5. 68Ge content / breakthrough: initially >10-3 % finally <10-7 % 6. low volume and low pH: 400 µl 0.05 N HCl / acetone further isolation of metalic impurities = high labelling yields = high specific activities eluted directly into labelling vial, containing amounts of precursor, e.g. 10-20 µg (7-14 nmole) DOTATOC, and an appropriate volume of water, without (or with) using buffer systems (5 ml water + 0.4 ml N2 = pH 2.3) >95% labelling at 10 min > 450 MBq / nmol DOTATOC ca. 65% yield referred to initially eluted 68Ga

Zhernosekov KP, Filosofov DV, Baum RP, Aschoff P, Bihl H, Razbash AA, Jahn M, Jennewein M, Rösch F, Processing of generator-produced 68Ga for medical application. J Nucl Med 2007; 48: 1741

E Eppard, M Wuttke, PL Nicodemus, F Rösch Ethanol-based post-processing of generator-derived 68Ga toward kit-type preparation of 68Ga-radiopharmaceuticals J Nucl Med. 2014; 55: 1023-1028.

Was

te

1 2

CATION -EX

Gen

erat

or

Ga-

68

68Ga purified

CEX resin

ACET

ON

E

/ HCl

ETHA

NO

L / H

Cl

NaC

l / H

Cl

Cation exchange-based post-processing of 68Ga-eluate: A comparison of three solvent systems for labelling of DOTATOC, NO2AP(BP) and DATAm. Seemann J, Eppard E, Waldron BP, Ross TL Roesch F JARI 98 (2015) 54-9

Cation exchange-based post-processing technologies Various secondary eluents to desorb purified 68Ga from the cation exchanger

68G

e/68

Ga

gene

rato

r

Chelator /Ligand

Cation exchanger

∆t (∆T)

radiolabelled product free of 68Ge

generator elution

Elute 68Ga Ethanol / HCl

specific buffer

Removal of 68Ge

Pure 68Ga

Cation exchange-based post-processing technologies Why is the ethanol-based version in particular relevant ?

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16

Yiel

d (%

)

Time (min)

Water

Ethanol

70°C 20 nM 40 VOL-% ETHANOL

68Ga-DOTA-TOC vs. TEMPERATURE

Cation exchange-based post-processing technologies The impact of non-aqueous solvents

on radiometal-ligand complex formation

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16

Yiel

d (%

)

Time (min)

Water

Ethanol

70°C 20 nM 40 VOL-% ETHANOL

68Ga-DOTA-TOC vs. TEMPERATURE

0

20

40

60

80

100

0 1 10 100

Yiel

d (%

)

Concentration of ligand (μM)

20 2

68Ga-DOTA-TOC vs. PRECURSOR CONC.

95°C x nM 5´ 40 VOL-% ETHANOL

Cation exchange-based post-processing technologies The impact of non-aqueous solvents

on radiometal-ligand complex formation

CHELATORS

Link

er

Spac

er

TV

Biol

. Tar

get

Chel

ator

Met

al

99mTc ε 140 keV

6.0 h coordination chemistry

kit type syntheses

68Ga-Radiopharmaceutical Chemistry = co-ordination chemistry

68Ga β+ 1.9

67.7 m coordination chemistry kit type syntheses

[99m

TcVI

I O4]

-

[68G

aIII(H

2O) 6]

3+

Chelators for 68Ga-PET Old guard

N N

NN

O OHO

OH

OHO

DOTA

O

HO

log K = 21

pH 4.6, 90°C, 30 min

tability - macrocyclic effect

Speciation?

NN

O OHO

OH

R

NN

RO

OH

Harsh labelling conditions

NN

RO

NN

N

OOH

O

HOO

HO

NOTA

pH 3 - 5.5, 25°C, 10 min

log K = 31

High kinetic stabi

Preorganised for Ga chelation

OOH

OOH

Chelators for 68Ga-PET New Challengers

NH HN

N N

OOH

OHO

H2DEDPA

NN

O

HOHO O

OH

HO

HBED

HN

O

NH

O

N

OHO

HNO

N

HOO

NHO

NOH

O

CP256

log K = 39

pH 3.6, 25°C, 10 min pH 4.5, 25°C, <10 minlog K = 28

pH 5.5 - 6.5, 25°C, <5 minGa(III) vs Fe(III) selectivity?

Kidney accumulation - stable?

NN

O

HOHO O

OH

HO

O

HN

OH

O

R

NH NH

O

N

OHO

HNO

N

HOO

NHO

NOH

O

NH

NH

OO

R

NH HN

N N

OOH

OHO

HNR

N N

N N

OOH

OHO

HN

R

HN

R

Fast radiolabelling kinetics - more flexible acyclic chelators

NN

HN

OH

O

OOH

OHO

NN

OH

O

OOH

HN

OHO

NN

HN

OH

O

OOH

OHO

NN

OH

O

OOH

N

OHO

DATAM DATA-p DATA-pPDATA-mP

NH

NN

OH

O

OOH

O OH

'Cyclic' donors

Acyclic donors

Diazepine-6-Amino-TriAcetate

(DATA)

Chelators for 68Ga-PET Newest Challenger: DATA

> 95 % RCY are obtained with: 4 post-processing methods for 68Ga versatile room temperature mild < 10 min fast

RCY

/ %

40

50

60

70

80

90

100

1 min 3 min 5 min 10 min

EtOH

fractionation

acetone

NaCl

DATA5M-TOC proof-of-principle for a kit-type synthesis

RCY > 95 % with all PP methods

at 25 °C (15 nmol)

99mTc ε 140 keV

6.0 h

HNN

H

HN

NH

NHNH

HN

O

O

O

O

O

O

O

NH2

OH OH

S SNH

OH

HO

NN

N

O

HN

OOH

OH

O

O

OH

GENERATORS

CHELATORS

FROM DOTA TO NOTA

FROM NOTA TO DATA

FROM TETRA- AND TRI-AZA CYCLOS

TO NON-MACROCYCLES

STILL 68Ge ISSUES

QUANTITATIVE 68Ga-LABELLING = NO NEED FOR PRODUCT PURIFICATION = KIT-TYPE 68Ga-RP = NO OPTION TO ISOLATE 68Ge POST-SYNTHESIS

Chelators for 68Ga-PET Approaching 99mTc-KIT-type preparation of PET-RPs

GENERATORS

CHELATORS


68Ga-Radiopharmaceuticals: proof-of-principle: 68Ga-DOTA-TOC NEUROENDOCRINE TUMORS

0:20 p.i. 0:40 p.i. 1:00 p.i. 1:20 p.i. 1:40 p.i.

NH

HN

NH

HN

HN

HN

NH

HN

HO

O

O

O

OO

O

O

SS

HO HO

NH2

NH

OH

HO

O N

N N

N

HO

O

OH

O

O

Agonists

Octreotides Targeting Somatostatin GPCR: Variation of amino acid sequences Variation of chelates HR Mäcke | J-C Reubi DOTA-TATE DOTA-NOC NOTAGA-TOC

• Antagonists have more binding sites than agonists

but show no accumulation via internalization.

• Sst2 and sst3 antagonists show superior pharmacological properties to agonists with similar or even lower receptor affinity.

Antagonist

Agonist

Radiopeptides Targeting GPCR: Agonists vs. Antagonists HR Mäcke | J-C Reubi

02.09.14

111In-Octreoscan sst2 receptor scintigraphy 24 h p.i. sst2 receptor agonist

68Ga-DOTATOC PET 1 h p.i. sst2 receptor agonist

14.11.14 18.11.14 68Ga-OPS202 PET 1 h p.i. sst2 receptor antagonist

past

present

future?

Radiopeptides Targeting GPCR: Agonists vs. Antagonists HR Mäcke | J-C Reubi

D W

ILD,

UN

IVER

SITY

HO

SPIT

AL B

SEL,

SW

ITZE

RLAN

D

68Ga-Radiopharmaceuticals: PROSTATE CANCER: PSMA-LIGANDS

Bioconjugate Chem. 2012, 23, 688−697

[18F]FECH PET/CT was unable to detect any lesions. However, 68Ga-PSMA PET/CT did show a lesion adjacent to the urinary bladder compatible with tumour relapse initial experience with 68Ga-PSMA PET/CT strongly suggests that this novel method can detect prostate carcinoma relapses and metastases with significantly improved contrast compared to 18F-FECH PET/CT.

[18F]FECH

[86Ga]HBED-CC

DKFZ

HEI

DELB

ERG

| 20

11

Cholin-PET/CT PSMA-PET/CT

68Ga-Radiopharmaceuticals: PSMA-LIGANDS vs. BONE METS

[68Ga]HBED-CC

DTZ

BERL

IN |

W M

OHN

IKE

| 20

14

68Ga-Radiopharmaceuticals: PSMA-LIGANDS vs. LYMPH NODES

DTZ

BERL

IN |

W M

OHN

IKE

| 20

14

PSMA-PET/CT [68Ga]HBED-CC

TRAP a scaffold for multifunctional tracer design

68Ga-Radiopharmaceuticals: αvβ3 INTEGRINES

Monomers / Trimers

TECH

NIC

AL U

NIV

ERSI

TY M

UN

ICH,

GER

MAN

Y

PET/MR: fusion

PET/MR: T2w MRI

PET/MR: PET ax

Pancreatic Adenocarcinoma / Liver Met.

PET/MR ax PET/MR sag PET/MR cor

Pancreatic Adenocarcinoma

Pancreatic Adenocarcinoma

PET/MR: PET PET/MR: fusion

[68Ga]TRAP(RGD)3

68Ga-Radiopharmaceuticals: αvβ3 INTEGRINES

TECH

NIC

AL U

NIV

ERSI

TY M

UN

ICH,

GER

MAN

Y

ON

NON

O

N

O

O

N H

HH

H

HO

HN

O N

N

N

N

O

OH

OO

HO

O

OH

HN

HNNH2

NH

compound IC50 [nM]

FC131 4.43 ± 0.82

DOTA-CPCR4-2 177 natGa-DOTA-CPCR4-2 4.99±0.72

68Ga-DOTA-CXCR4

68Ga-Radiopharmaceuticals: CXCR4-LIGANDS FOR CHEMOKINE RECEPTORS

tumorigenesis, proliferation, …

TECH

NIC

AL U

NIV

ERSI

TY M

UN

ICH,

GER

MAN

Y

[68Ga]Pentixafor

Uptake in Stem Cell Niches of the Bone Marrow

TECH

NIC

AL U

NIV

ERSI

TY M

UN

ICH,

GER

MAN

Y


[68Ga]Pentixafor

68Ga-Pentixafor

18F-FDG

myeloma

Collaboration with K.Herrmann, A.Buck, S.Knop, M.Lassmann, Dept. Nuclear Medicine, Med.Klinik und Poliklinik II, Universität Würzburg, GER

TECH

NIC

AL U

NIV

ERSI

TY M

UN

ICH,

GER

MAN

Y


Peptidic 68Ga-Radiopharmaceuticals: Established systems and future developments

GPC-Receptors

Targets Tools in vivo targeting in man

SS Neuroendocrine tumors, Meningnomas Medulloblastomas

+ +

GLP1 Insulinoma + +

GIP GI NET, MTC (+) -

NT Ductal pancreas Ca + (+)

GRP Prostate Ca, Breast Ca, Ovarian Ca + +

CCK GEP tumors + (+)

NPY Breas Ca, Ewing Sa, Glioblastomas - (+)

MCR-1

PO3H2

PO3H2

R1

R2

N

N N

N

OH

O

HO

O

O

HO

O

R

+

combination of a macrocyclic chelator … with a bis-phosphonate (BP) moiety:

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

68Ga-Radiopharmaceuticals: BONE METASTASES: BISPHOSPHONATES

Bisphosphonates for PET/CT 1st Human Application

57 year old male patient with primary prostate cancer

wide spread bone metastases 462 MBq [68Ga]BPAMD

(i.v.; PET 50 min p.i.) PET (left, coronal) and

PET-CT (right, sagital)

Fellner M et al. Eur J Nucl Med Mol Imag 2010; 37:834

PET, CT and PET-CT (top to bottom), transversal slices

Baum

RP.

Dep

t. of

Nuc

lear

Med

icin

e/P.

E.T.

Cen

ter,

Zent

ralk

linik

Bad

Ber

ka

N

N N

N

O

NH

PO(OH)2

PO(OH)2

COOH

HOOC

HOOC

[99mTc]MDP [68Ga]NO2APBP [18F]NaF

AIIM

S N

EW D

ELHI

| A

. MAL

HOTR

A +

CS B

AL

PO PO(OH)2

PO(OH)2NN

N

COOH

HOOCOH

[68Ga]NO2APBP human studies vs. 18F- and [99mTc]MDP

[68Ga]DOTAMPAM

[68Ga]DOTAMZOL

[68Ga]BPAPD

*P ≤ 0.05

* *

*

*

* *

Wistar rat (N = 5) 140-220 g 8-10 MBq 1 h p.i.

lung liver spleen kidneys muscle heart blood intestine femur

New 68Ga-DOTA-Bisphosphonates: α-H vs. α-OH

MIK

E SA

THEK

GE, U

NIV

ERSI

TY O

F PR

ETO

RIA

& S

TEVE

BIK

O A

CADE

MIC

HO

SPIT

AL, R

EP. O

F SO

UTH

AFR

ICA 1st Patient Study [68Ga]DOTAMZOL

New 68Ga-DOTA-Bisphosphonates: α-H vs. α-OH

68Ga β+ 1.9 67.7 m

coordination chemistry kit type syntheses

generator-based

68Ga-Octreotides 68Ga-PSMA

68Ga-Bisphosphonates

68Ga-CXCR4 68Ga-RGD

PET /CT

promising oncological 68Ga radiopharmaceuticals for PET/CT diagnoses … so what?

68Ga-MORE…

Concept: general

M O L E C U L E

THERANOSTICS

Theranostics Theranostics means the increasingly close interlocking of Diagnosis and Therapy. Aim is to allow for the right therapy for the right person at the right time. is the therapy-accompanying diagnosis with the aim of a patient-specific treatment. Main constituents are: -Characterisation of the genetic predisposition -Characterisation of the stadium of the disease -Monitoring of the success of the treatment process Including the determination of -the efficacy of a therapeutic drug -for a given disease -for an individual patient. theranostics in the angloamerican world: = personalized medicine and predictive medicine.

WANTED

(available)

matched pairs of therapeutic & PET nuclide

Concept related to nuclear and radiopharmaceutical chemistry

for therapy for diagnosis

M O L E C U L E

THERANOSTICS

Theranostics Theranostics means the increasingly close interlocking of Diagnosis and Therapy. Aim is to allow for the right therapy for the right person at the right time. is the therapy-accompanying diagnosis with the aim of a patient-specific treatment. Main constituents are: -Characterisation of the genetic predisposition -Characterisation of the stadium of the disease -Monitoring of the success of the treatment process Including the determination of -the efficacy of a therapeutic drug -for a given disease -for an individual patient. theranostics in the angloamerican world: = personalized medicine and predictive medicine.

[86Y]Citrate-PET: Short and long kinetics

Time p.i. [min]0 10 20 30 40 50 60

86Y

act

ivit

y co

ncen

trat

ion

[nC

i/cc]

0

200

400

600

800

1000

metastasis

kidneys

liver

4 h p.i.

24 h p.i.

36 h p.i.

72 h p.i.

48 h p.i.

86Y-PET vs. 90Y-ERT

Rösch F, Qaim SM, Stöcklin G. Nuclear data relevant to the production of the positron emitting radioisotope 86Y via the 86Sr(p,n)- and natRb(3He,xn)-processes. Radiochim Acta 61 /1/ (1993) 1-8

Rösch F, Qaim SM, Stöcklin G. Production of the positron emitting radionuclide 86Y for nuclear medical application. Int J Appl Radiat Isot 44 /4/ (1993) 677-681

estimated organ doses for 90Y-Bone Mets

FZ JÜLICH & NUKMED AACHEN / SM QAIM & G STÖCKLIN & H HERZOG

86Y

mean radiation doses [90Y]Citrate vs. [90Y]EDTMP [mGy / MBq 90Y injected]

90Y- complex

Bone metastases (per cc)

red bone marrow (total)

liver (total)

Citrate

25.5 10.6 2.5 0.4 1.8 0.3

EDTMP

17.8 1.7 1.8 0.6

-

86Y-PET vs. 90Y-ERT

Herzog H, Rösch F, Stöcklin G, Lueders C, Qaim SM, Feinendegen LE. Measurement of pharmacokinetics of yttrium-86 radiopharmaceuticals with PET and radiation dose calculation of analogous yttrium-90 radiotherapeutics. J Nucl Med 34 (1993) 2222-2226

Rösch F, Herzog H, Plag C, Neumaier B, Braun U, Müller-Gärtner HW, Stöcklin G. Radiation doses of yttrium-90 citrate and yttrium-90 EDTMP as determined via analogous yttrium-86 complexes and positron emission tomography. Eur J Nucl Med 23 (1996) 958-966

estimated organ doses for 90Y-BM

FZ JÜLICH & NUKMED AACHEN / SM QAIM & G STÖCKLIN & H HERZOG

86Y

2 h p.i. 30 h p.i. 23 h p.i. 12 h p.i. 7 h p.i. 4,5 h p.i. 1 h p.i. (max. pixel projection)

5 h p.i. 24 h p.i.

86Y-PET vs. 90Y-ERT estimated organ doses for 90Y-DOTATOC

UM MAINZ / UNI TÜBINGEN

86Y

estimated organ doses for 90Y-DOTATOC

organs t organ (h)

D organ (mGy/MBq)

Intestine wall - 0.05 ± 0.002

kidneys 1.51 ± 0.78 2.73 ± 1.41

liver 2.33 ± 0.53 0.660 ± 0.002

other tissue - 0.05 ± 0.002

red marrow 0.04 ± 0.01 0.05 ± 0.002

spleen 0.79 ± 0.67 2.32 ± 1.97

urinary bladder wall 0.78 ± 0.17 1.03 ± 0.23

remainder of the body 6.36 ± 0.21 -

Total body - 0.08 ± 0.01

Effective dose (mSv/MBq) 0.22 ± 0.07

86Y-PET vs. 90Y-ERT

UM MAINZ / UNI TÜBINGEN

86Y

for therapy M O L E C U L E

THERANOSTICS for diagnosis

177Lu β- 0.6 6.4 d

68Ga β+ 1.9

67.7 m

TV

Biol

. Tar

get

M O L E C U L E

THERANOSTICS

Chelates satisfying both 68Ga and 177Lu co-ordination chemistry ?

old DOTA

simply the best

95°C 10-15 min for 68Ga 20-30 min for 177Lu

before PRRT-1 4 GBq Y-90 SUV 15.8

3-mo after PRRT-1 SUV 8.4

before PRRT-2 4.5 GBq Lu-177

SUV 9.3

18-mo after PRRT-3 SUV 3.4

before PRRT-3 5.5 GBq Lu-177

SUV 6.9

Persisting Complete

Remission!

68Ga-analogue Radiotherapeuticals 68Ga/90Y/177Lu-DOTA-Tyr3-octreotides vs. PRRT

68Ga SUVmax and therapy response

68Ga β+ 0.74 89.1% 67.7 m 90Y

β- 2.3 … .

64.1 h

68Ga β+ 0.74 89.1% 67.7 m

68Ga β+ 0.74 89.1% 67.7 m

68Ga β+ 0.74 89.1% 67.7 m

68Ga β+ 0.74 89.1% 67.7 m 177Lu

β- 0.6 … .

6.71 d

177Lu β- 0.6 …

. 6.71 d

BAD

BERK

A |

R. B

AUM

68Ga-Radiopharmaceuticals: PROSTATE CANCER: PSMA-LIGANDS

DKFZ

HEI

DELB

ERG

| 20

11

68Ga-analogue Radiotherapeuticals 177Lu-DOTA-PSMA derivatives

From HBED to DOTA | DOTAGA Variation of the linker ✕

68Ga-analogue Radiotherapeuticals 177Lu-DOTA-PSMA derivatives

Pretherapy Ga-68 PSMA PET/CT Local prostate cancer involving the seminal vesicles with lymph node and extensive bone metastases.

3 months post Lu-177 PSMA Therapy Excellent response to radioligand therapy. Most of the intense PSMA positive metastases not discernible. TH

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45 h p.i.

Excellent tracer uptake in abdominal LN metastases from SCLC

PRLT Lu-177 CXCR4 SPECT/CT

68Ga-analogue Radiotherapeuticals 177Lu-DOTA-CXCR4 ligands

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5 GBq [177Lu]BPAMD / monitored with SPECT / over 24 h p.i.

0.5 h p.i. 3.0 h p.i. 23 h p.i.

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HOOC68Ga-analogue Radiotherapeuticals

177Lu-DOTA-Bisphosphonates

DTZ BERLIN | 23.03.-26.03.2015

Szintigraphic images of patient developed with [99Tc]MDP (A) and 223RaCl2 on day 0 (B), day 2 (C) and day 6 (D) p.i.

ante post

223Ra (Xofigo)

day 1

New 177Lu-DOTA-Bisphosphonates: [177Lu]DOTAMZOL

*John L. Humm et al. Radium-223 in the Treatment of Osteoblastic Metastases: A Critical Clinical Review, Int J Radiation Oncol, 2014; 91: 898-906

*Me(III)-THERANOSTICS in Nuclear Medicine

68Ga β+ 1.9

67.7 m

ERT PET /CT

177Lu β- 0.6 6.4 d

90Y β-

2.3 d 213Bi α

56 min

68Ga β+ 1.9 67.7 m

thyorid

lung

liver

kidney

Non-oncological 68Ga radiopharmaceuticals ?

infection

Brain tumors

Brain dysorders

heart

GMP-like, registered

Beyond DOTA: Complex formation:

short time, low temperature,

low pH, high yield

Easy to conjugate (KIT)

Accessible for 177Lu

multi-dentate, multi-functional „click-able“

pre-targeting

Broad indications: main tumors heart brain etc.

GMP-like, registered (KITs)

GENERATORS

CHELATORS


COMMERCIAL KITS


THERANOSTICS

68Ga: A running wheel

68Ga is becoming The most predictive nuclide for therapy

GENERATORS

CHELATORS


COMMERCIAL KITS


THERANOSTICS

68Ga: A running wheel

World Congresses on Gallium-68 and

Peptide Receptor Radionuclide Therapy (PRRNT) THERANOSTICS –

on the way to personalized medicine

… from 1st (Bad Berka & Mainz, Germany, 2011) world congress ... 2nd (Chandigarh, India, 2013)

3rd (Baltimore, USA, 2015) to 4th in Melbourne, November 07-09, 2016

Ga radiopharmaceuticals: Current status and future radiopharmaceuticals: Current status and future ....

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