International Atomic Energy Agency
Development of Lu-177 based Radiopharmaceuticals for Radionuclide
Therapy
M.R.A. PillaiIndustrial Applications and Chemistry
International Atomic Energy Agency
•Review of radioisotopes requirements for therapy
•Review some of the therapeutically useful radionuclides and the feasibility of production
•Advantages of Lu-177 as a therapeutic radionuclide
•Production logistics of Lu-177 •Some of the Lu-177 radiopharmaceuticals
•IAEA programs on Lu-177
Goals of Presentation
International Atomic Energy Agency
Radionuclide Therapy
• Hyper thyroidism• Treatment of cancer• Bone pain palliation agents• Radiosynovectoy for Rheumatoid arthritis
• Radionuclide therapy started with 131I and 32P and these isotopes continue to occupy a role in nuclear medicine
International Atomic Energy Agency
Why 32P and 131I is widely used?
• Both 32P and 131I can be prepared in medium flux reactors in adequate quantities
• The isotopes are of high specific activity due to the production route followed
• The Worldwide use of 32P and 131I is feasible • Logistics of production • Ability to move the isotope around the globe
• High specific activity
International Atomic Energy Agency
Radionuclide therapy beyond 131I and 32P
• Despite the several advantages of 131I and 32P, these isotopes have limited use for development of radiopharmaceuticals for targeted therapy of cancer
• The large percentage of gammas in the case of 131I and the high energy beta particles of 32P are not ideal for targeted therapy
• Thus there is a need for other isotopes for therapy
International Atomic Energy Agency
Can we find a match equivalent to 99mTc for therapy?
• About 10-15 million diagnostic investigations are done per year the world over
• Oncology studies are increasing rapidly, more so with 18FDG
• Targeted therapy using radionuclides are likely to take a great leap in cancer therapy
• If 1 % of the diagnostic investigations need RNT, 100,000 therapy doses are needed per year
• A few million Curies of therapeutic radionuclides are needed, If 100,000 patient doses are to be delivered
• If that is the case, what are our options?• Which are the most favourable isotopes?
International Atomic Energy Agency
- Emitting Radionuclides for Therapy Short Range Medium Range Long Range
T1/2
T1/2 T1/2
199Au 3.1 153Sm 1.9 165Dy 0.1169Er 9.3 143Pr 13.6
89Sr50
175Yb 4.2 170Tm 128.6 32P 14177Lu 6.7 198Au 2.7 166Ho 1.167Cu 2.6 111Ag 7.5 188Re 0.7105Rh 1.5 109Pd 0.5 142Pr 0.847Sc 3.4 186Re 3.8 90Y 2.7131I 8.0
International Atomic Energy Agency
Selection of a Therapeutic Radionuclide
• Half life- Advantagoues to have a long half life (few days)
• Mode of Decay- - is the choice • Energy of the - particles (Depends on the application, but low energy preferred)
• Availability of gamma photons• Specific activity
International Atomic Energy Agency
Augers – Intracellular – Pt-195mAlphas– 5-8 Cell Diameters – Th-229
Range of Electrons in Soft Tissue(Maximum Beta Energy)
10
1
0.1
0.01
0.001
Rang
e (m
m)
0.1 0.2 1 2 10Electron Energy (MeV)
Lu-177
Re-186
Y-90
P-32
Re-188Sm-153
Sn-117m (CE)
ORNL 2000-0614b/rra
International Atomic Energy Agency
Specific activity
The availability of the RN in carrier free form is desirable for many applications
• Generators offer carrier free radionucldies• 188W-188Re Generator• 90Sr-90Y Generator
International Atomic Energy Agency
AvailabilityWhat are the radionuclides that can be
produced easily, processed and shipped ?
International Atomic Energy Agency
188Re
• 188Re is useful for several of the therapeutic applications
• Available from a generator (188W-188Re)
• Available carrier free and of very high specific activity from the generator
• 188W is difficult to be produced
International Atomic Energy Agency
Rhenium-188 is Formed by Decayof the Tungsten-188 Parent
Production and Decay Scheme for Tungsten-188
ORNL 2003-02191/rra
High Flux Mandatory forProduction of Sufficient Sp. Act
International Atomic Energy Agency
188WYield vs. Flux
____________________________
Flux (n/cm2.sec) Specific activity
(mCi/g of W)
___________________________________ 1x 1013 0.336
1x 1014
33.361x 1015 3017
___________________________________
International Atomic Energy Agency
188W-188Re Generator
• There are only two reactors in the World which can make reasonable quantities of 188W
• ORNL in USA and Dimitrograd in Russia• The production capacity together is a few hundred Ci per year
International Atomic Energy Agency
153Sm • 153Sm is widely used as a radionuclide for bone pain palliation
• The isotope can be prepared in medium flux reactor in adequate quantities
• Specific activity is good for making bone pain palliation agents
• Short half life of 47 h precludes its wide use
International Atomic Energy Agency
90Y• Generator produced isotope • High specific activity from the generator
• 28 Y half life of 90Sr enables the use over a long time
• Large stock of 90Sr is present in the World as nuclear waste
• The countries having nuclear waste can separate 90Sr and supply for the entire global demand
• A useful option when high energy beta particles are needed
International Atomic Energy Agency
The therapeutic radionuclide of choiceLu-177
• Lu-177 will emerge as a major therapeutic radionuclide
• About 30 clinical studies are currently going on with Lu-177
• Major suppliers are offering Lu-177 as a radiochemical
International Atomic Energy Agency
Some Major Advantages for WidespreadUse of Lutetium-177 for Therapy
ORNL 97-5097a/rra
• Beta Energy - β max = 0.497 MeV (50%) – Low tissue penetration – advantages for targeting microstatic disease
• Imaging - 111 keV gamma (6.7%) for imaging• Half-life – 6.7 days - major advantage - permits
broad distribution• Chemistry - + 3 metal – forms strong chelates – DOTA/phosphonates, etc.
• Production - Lu-177 can be produced with high specific activity in a large variety of research reactors worldwide
International Atomic Energy Agency
Lu-177
• Bone pain palliation studies• Targeted therapy of cancer and metastasis
• Medium and small joint synovectomy
• Easy to produce
International Atomic Energy Agency
Lu-176
Lutetium-177 Is Usually Produced by the Direct – Radiative Route from Enriched Lu-
176
ORNL 2000-06539a/rra
Yb-176
Lu-177 6.89 days
Yb-177 1.9 hours
Lu-177m 160 days
+n, g
n, g
σ = 2090 barrn
σ = 2.85 barn
Direct Route
Beta Decay Route Provides Carrier-Free
routeImproved/optimized separation requiredNot preferred
Indirect Route Beta Decay
International Atomic Energy Agency
Activity Produced for Different Isotopes
• 5 day irradiation at a Flux of 5x1014 n/cm2.sec
• Assuming 100% Abundance• If target burn-up is considered the activity produced for 177Lu will be ~ 30500 Ci/g
89Sr 99Mo 153Sm 177Lu
Cross section(barns)
0.0058
0.13 206 2100
Activity produced(Ci/g)
0.0035
7.7 9150
39000
International Atomic Energy AgencyORNL 2005-0203/jcn
“Direct” Production of Lutetium-177 from Lutetium-176 Target
Acti
vity (
Ci/mg)
176Lu T
arget
0 5 10 15 20 25
70
60
50
40
30
0
10
4-5 x 1014 n cm-2 s-1 (thermal)1 x 1012 n cm-2 s-1 (epithermal)
ORNL HFIR
Irradiation Time (Days)
20
“Direct” Production of Lutetium-177 from Enriched Lutetium-176 Target
2 x 1015 n cm-2 s-1 (thermal)1 x 1014 n cm-2 s-1 (epithermal)
1 x 1014 n cm-2 s-1 (thermal)1 x 1012 n cm-2 s-1 (epithermal)
30% of TheoreticalHANARO - MURR
177Lu Theoretical Specific Activity = 109 Ci/mg
High thermal neutron cross section – σ = 2090 barnsHigh Flux Allows near Theoretical Specific Activity
International Atomic Energy Agency
177Lu from 176Yb
• Can also be produced by (n,g) activation followed by beta decay
• 176Yb (n,g) 177Yb 177Lu• 2.4 barns• Enriched 176Yb needed• Theoretical specific activity 1.09x105 Ci/g
• Not preferred route
International Atomic Energy Agency
177Lu from 176Yb• Practical specific activity will be limited by the decontamination/separation possible from Yb
• Inactive Yb present will compete with Lu for complexation
• The practical specific activity will be similar to the direct production route
• Difficult to produce in large quantities
• More of theoretical interest than of practical utility
International Atomic Energy Agency
177Lu: holds great promise
• Heaviest lanthanide, but Lu+3 has 89.1 pm ionic radius in coordination number 6, which is 4 pm smaller than Y+3
• Highly stable +3 oxidation state (4f 0 system)
• Very high stability of 8/9 co-ordinated chelates with N,O,P,S donor ligands
Metal Stability Const. (M-1) with DTPA
Lu 2.51x1022
Y 1.12 x1022
Sm 6.84 x1021
____________________________________________________
International Atomic Energy Agency
Gamma-ray spectrum of 177Lu
0 1000 20001
10
100
1000
10000 72 keV
(177 Lu)
250 ke
V(17
7 Lu)
321 ke
V(17
7 Lu)
113 ke
V (17
7 Lu)
208 ke
V (17
7 Lu)
Net cou
nts (lo
g scale)
C hannel num ber
Radionuclidic purity of 177Lu achievable is 99.985%
The average level of radionuclidic impurity burden in 177Lu due to 177mLu found to be 5.5 kBq of 177mLu / 37 MBq of 177Lu (150 nCi / 1 mCi) at EOB
International Atomic Energy Agency
Production of 177Lu• IrradiationNatural (2.6% 176Lu) or enriched (60.6% 176Lu) Lu2O3 irradiated in Dhruva for 5-7 d at 31013 n/cm2/s
• Chemical processing Dissolution in 0.1 M HCl to obtain LuCl3 used for labeling
Specific Activity 2.8-3.5 Ci/mg for enriched Lu
Radionuclidic purity by g ray spectrometry >99.99%, 5.5 kBq 177mLu/ 37 MBq 177Lu (150 nCi/ mCi)
International Atomic Energy Agency
177Lu is an attractive radionuclide for bone pain palliation and Tumour
therapy• Low energy particles and hence minimum dose to bone marrow (as against 32P or 188Re)
• Easy and economical production in large scale
• 6.71 d half-life is convenient and there is considerably less decay loss unlike 153Sm
• Most of the activity prepared at EOB can be used in patients
• Lower patient dose: Requirement is much less due to higher cumulative dose delivery unlike 153Sm
International Atomic Energy Agency
EDTMP or DOTMP?
• EDTMP forms good complex with 177Lu
• 153Sm-EDTMP is already an approved radiopharmaceutical and hence 177Lu-EDTMP will be acceptable
• The cyclic phosphonate DOTMP forms equally good complex with slightly better properties
International Atomic Energy Agency
DOTMP [1,4,7,10-tetraazacyclododecane-
1,4,7,10- tetramethylene phosphonic acid]
R = -CH2-P(O)(OH)2
R
RR
R R
R
HO P H
O
OH
- 4 H2O, 2hConc. HCl,
4+ H
C H
O
+ 4
R = H
, Cyclen
N
N
N
N
R
N
N
N
N
R
DOTM P
Characterized by FT-IR and 1H-NMR Spectroscopy
International Atomic Energy Agency
Preparation of 177Lu-DOTMP complex
Easy to produce: Mix and leaveDOTMP dissolved in 0.4 mL, 0.5 M
NaHCO3 solution (pH 9)+
0.5 mL normal saline +
0.1 mL of 177LuCl3
Adjust PH to 7 and incubate at RT
International Atomic Energy Agency
Biological Evaluation of 177Lu-DOTMP
Biodistribution pattern in Wistar rats
3 h 1 d 2 d 7 d
8
6
4
2
0
Time p.i.
% ID/gBlood Liver Kidney Tibia
International Atomic Energy Agency
177Lu-DOTMPScintigraphic images in rabbits
1 h post-injection
24 h post-injection
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177Lu- Targeted tumor therapy
• 2 mm soft tissue penetration • Ideal for small lesion • g photons in low abundance suitable for imaging• Specific activity is adequate for targeted therapy
International Atomic Energy Agency
177Lu-DOTA-LanreotideSomatostatin receptors are Over- expressed in a
variety of cancers Majority of neuroendocrine tumors
Neuroblastomas Some medullary carcinomas Prostate cancer Small cell lung cancerLanreotide, a somatostatin analog, is used in the treatment of neuroendocrine tumors
International Atomic Energy Agency
Structure of DOTA-Lanreotide
H
ONH
NH
ONH
SH
O O HHN
H
H
O
HN
NH2
HN OH
H
O
NHH3CCH3
H
H
SO
HN
HCONH2
H
O HH3C
(Ala)
(Cys)(Cys)
(Tyr)
(Trp)(Lys)
(Val)
(Thr)
LANREO TIDE
NN
NN
COOH
COOH
HOOC
C
O
N
-DO TA
International Atomic Energy Agency
Labeling of DOTA-Lanrotide with 177Lu
Protocol 25 g of DOTA-Lanreotide dissolved in 0.5 M NaHCO3 (pH ~9)
177Lu ( ~100 MBq/g) pH adjusted to ~5 2 h incubation at 37C
Complexation yield- ~80 %
International Atomic Energy Agency
HPLC Purification Gradient elution with acetonitrle-water
system
0 200 400 600 800 1000 1200 1400 1600 1800
0
50
100
150
200
250
300
U ncom plexed 177Lu
177Lu-D O TA -LanreotideCou
nts/se
c
R etention tim e
International Atomic Energy Agency
HPLC patterns 177Lu - DOTA-TATE (25g of peptide)
(A) After preparation (B) After 7 days
0 200 400 600 800 1000 1200 14000
50
100
150
200
250
(A )
Cou
nts pe
r sec
ond
R etention tim e (sec)0 200 400 600 800 1000 1200
0
50
100
150
200
250
(B )
Coun
ts per sec
ond
R etention tim e (sec)
International Atomic Energy Agency
Conclusion
• Large quantities of radioisotopes are needed for the treatment
• 177Lu holds great promise for wider application
• Large quantities of 177Lu can be prepared by irradiating either natural or enriched targets
• Medium Flux reactors can produce 177Lu for bone pain palliation
• High Flux reactors can be used for 177Lu for targeted therapy
• A 100 mg of enriched 176Lu irradiation for five days in a high flux reactor (1x1015 n.cm2.sec) can give 7000 Ci of 177Lu
International Atomic Energy Agency
Coordinated Research Project for the development and use of radiopharmaceuticals
based on 177Lu• Two CS meetings (Radiopharmaceutical & Clinical) planned in May 2006
• Two CRPs will be announced shortly• CRP on ‘Development of 177Lu based radiopharmaceuticals for radionuclide therapy’
• CRP for the ‘Use of 177Lu-EDTMP/ phosphonates for bone pain palliation of patients suffering from in prostrate cancer’
• CRPs will start in 2006, first RCM in last quarter of 2006
• Phase I/II Clinical trials to be completed by the end of the CRP
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