Lutetium-177 radiopharmaceuticals, Manila, Philippines, 2009

International Atomic Energy Agency

Development of Lu-177 based Radiopharmaceuticals for Radionuclide

Therapy

M.R.A. PillaiIndustrial Applications and Chemistry

[email protected]


•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


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


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


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


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?


- 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


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


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


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


AvailabilityWhat are the radionuclides that can be

produced easily, processed and shipped ?


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


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


188WYield vs. Flux

____________________________

Flux (n/cm2.sec) Specific activity

(mCi/g of W)

___________________________________ 1x 1013 0.336

1x 1014

33.361x 1015 3017

___________________________________


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


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


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


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


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


Lu-177

• Bone pain palliation studies• Targeted therapy of cancer and metastasis

• Medium and small joint synovectomy

• Easy to produce


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


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


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


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


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

____________________________________________________


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


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)


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


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


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


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


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


177Lu-DOTMPScintigraphic images in rabbits

1 h post-injection

24 h post-injection


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


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


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


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 %


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


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)


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


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

Lutetium-177 radiopharmaceuticals, Manila, Philippines, 2009

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