ga radiopharmaceuticals: current status and future radiopharmaceuticals: current status and future ....
TRANSCRIPT
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
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.
The PET 68Ge/68Ga generator 68Ga-eluate purity / 68Ge breakthrough recommendations
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.
The PET 68Ge/68Ga generator 68Ga-eluate purity / 68Ge breakthrough recommendations
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
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
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-Radiopharmaceuticals: CXCR4-LIGANDS FOR CHEMOKINE RECEPTORS
[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
68Ga-Radiopharmaceuticals: CXCR4-LIGANDS FOR CHEMOKINE RECEPTORS
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
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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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
NEW CHEMISTRY NEW TRACERS
COMMERCIAL KITS
PET/CT FOR MAIN INDICATIONS
THERANOSTICS
68Ga: A running wheel
68Ga is becoming The most predictive nuclide for therapy
GENERATORS
CHELATORS
NEW CHEMISTRY NEW TRACERS
COMMERCIAL KITS
PET/CT FOR MAIN INDICATIONS
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