Time to prepare alpha emitting

therapeutic radionuclide production

Dongguk Univ._Gyeongju

Kim, Sang Wook

• Radioisotope (RI) and Production

• Importance of α-particles

• Obstacles

• Alternatives

• Conclusion

Contents

Radioisotope (RI)

• To produce or develop RI

• Find nuclear reaction such as [18O(p,n)18F] and determine the

methods

• Calculate the cross section with code (ex: SRIM)

Radioisotope (RI)

Radioisotope (RI)

p18O

H H

p

targetVacuum

Cyclo

tron

Metal foil

Helium coolant

n18F

Water coolant

Radioisotope (RI)

209Bi (α, 2n) 211At (A)

• Accelerator or reactor

• Targetry

• Chemical separation

• Generator or waste harvesting

Radioisotope (RI)

Accelerator and reactor

Targetry

Chemical separation

Generator

68Ge/68Ga generator

(Obninsk, Russia)

(Eckert & Ziegler, Germany)

(iThemba LABS, SAF)

Radioisotope (RI) to Radiopharmaceuticals

O18F NH2

COOH

[18F]FET

O

18F

HO

HN

N

O

O

CH3

[18F]FLT

1. A →→→→B2. Labeling

2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) synthesis

OOH

18F

HO

HOHO

OOAc

18F

AcO

AcOAcO

OOAc

AcO

AcOAcO

OTf

MeCN

18F-,PTC 1N HCl

Triflate F-18 fluorination Hydrolysis [18F]FDG

Radiopharmaceuticals

Y-90 labelled zevalinTarget specificcompounds

Chelate withRI (M)

Linker

223RaCl2 application

Irradiates adjacent tumor cells

Alpha-particl

e radiation

Bone marrow

Osteoblast

Newly formed bone

Ra-223

depositionOsteoblast

Tumor

cells

Targets new bone in

metastases

- Phase III clinical trials for therapy of prostate cancer have been successfully completed;

- Phase II clinical trials for therapy of breast cancer are now being performed.

Radiopharmaceuticals [Xofigo® (Alpharadin) ®]

Approved by FDA

• A charged helium (4He2+) is heavier than other subatomic

particles such as neutrons and protons

• α-particles have high linear energy transfer (up to 100 keV/μm)

and a short pathlength (~ 50-100 μm) in comparison with β- p

articles

• α-particles can deliver approximately 1,500 times more

energy/unit path length than β- particles

• So, α-particles is ideal for the therapeutic purpose if can be

produced

Alpha particle (α)

• At-211 (7.2 h), Bi-212 (60.6 m), Bi-213 (45.6 m), Ac-225 (10.0 d),

Ra-223 (11.4 d) and Terbium-149 (4.1 h)

• Half-lives of Ra-223 (11.4 d) and Ac-225 (10.0 d) are suitable f

or manufacturing and therapeutic treatment;

• Emit multi α-particles in each decay chains providing a higher i

mpact;

• May be also used as generator of the short-lived isotopes:

225Ac → 213Bi (T1/2 = 46 min)

223Ra → 211Pb (T1/2 = 36 min).

Alpha particle (α)

Isotope Ac-225 Bi-213 Ra-223 At-211

T1/2 10.0 d 45.6 min 11.4 d 7.2 h

LimitationsLimited

availabilityLimited

availability-

Way of using directlyGenerator from

Ac-225

DirectlyByproduct

Ac-225cyclotron

Human studies

Refractory Multiple Myeloma, AM

L (ongoing)

Phase I and II ofleukemia, lymphoma, mal. melanoma, glio

ma

Phase III of prostate

cancer and phase II of

breast cancer

Not yet

Current international clinical trials with alpha particles

https://clinicaltrials.gov

Current international clinical trials with alpha particles

https://clinicaltrials.gov

Current international clinical trials with alpha particles

Infrastructure and capability in Korea

Operated by Capacity EA Purpose

Cyclotron

Hospital, Industry 7.5~18 MeV 28 FDG

CRC center by gov. 13 MeV 7 RI

KIRAMS

16.5 MeV 1 RI

30 MeV 1 RI

50 MeV 1 RI research

KAERI_ARTI 30 MeV 1 RI research

KAERI_Gyeongju 100 MeV 1RI research

LINAC

SKKU 9,13 MeV 2 Accel. research

Research reactor

HANARO 1 RI research and other

KJRR 1RI research and other

Under construction

• Infra structure [RI usage stat. from KARA (2014)]

Infrastructure and capability in Korea

• Capability in terms of RI development

RI Completness RI Completness

F-18 High I-131 High

C-11 High Ho-166 High

Ga-68 Med Lu-177 Med

Sc-44 Low Ir-192 High

Zr-89 Med-High Au-198 Med

I-123 High Re-188 High

I-124 Med

Tl-201 High

Ga-67 High

Cu-64 Med

Cu-67 Med

I-125 Low

Infrastructure and capability in Korea

<Main RI Production facility and their future mission>

① Cu & other theranostic② High specific Sn-117m③ Clinically applicable research with RI

KIRAMS

① Harvesting and fission for therapeutic② RTG③ C-14④ Enriched (SI)

HANARO/KJRR

① High power targetry② Mass production technique③ Calibration sourse

KAERI-Gyeongju

① Brachy therapy Pd-103 (seed) ② Scientific source (Chromatography, Moss bauer)③ RI generator

KAERI-ARTI

Differenciation&

Collaboration

Production of alpha particles_Ac-225 & Ra-223

• Half-lives of Ac-225 (10.0 d) and Ra-223 (11.4 d) are suitable for

manufacturing and therapeutic treatment.

• Ra-223 is a by-product of Ac-225 production.

• Emit α-particles in each decay chains provide more higher impa

ct.

• Can be also used as generator of the short-lived isotopes:

225Ac → 213Bi (T1/2 = 46 min)*

223Ra → 211Pb (T1/2 = 36 min).

Production of alpha particles_Ac-225, Ra-223, Bi-213

232Th (p, x) → 225Ac 232Th (p, x) → 227Th → 223Ra

Production of alpha particles_Ac-225, Ra-223, Bi-213

1. Long-term generator on the base of 229Th and 227Ac

229Th (7340 y) → 225Ac (chain of 235U) 227Ac (21.8 y) → 227Th (18.7 d) → 223Ra

2. Irradiation on fast and high-flux reactors226Ra (n, 2n) 225Ra → 225Ac 226Ra (n, γ) 227Ra (42.2 min) → 227Ac → 227Th → 223Ra

3. Irradiation with charged particles

226Ra (p, 2n) 225Ac 226Ra (p, p3n) 223Ra

226Ra (α, 3n) 227Th → 223Ra

232Th (p, x) → 225Ac 232Th (p, x) → 227Th → 223Ra

Excitation function of Ac-225

0

2

4

6

8

10

12

14

16

18

20

0 20 40 60 80 100 120 140 160 180 200Сum

ula

tive

cross

sec

tion o

f22

5 Ac

mbar

n

Proton energy, MeV

Ermolaev et al., 2012

Gauvin, 1962, 1963

Weidner et al., 2012

Zhuikov et al., 2011

Lefort et al., 1961

Excitation function of Ra-223

0

10

20

30

40

50

60

0 20 40 60 80 100 120 140 160 180 200

Сum

ula

tive

cross

sec

tion

223 R

a

mbar

n

Proton energy, MeV

Th-227, Ermolaev et al,

2012Th-227, Lefort et al., 1961

Th-227, Hogan et al., 1979

Th-227, Weidner et al.,

2012

Production routes for Ac-225

233Pa*232Pa1.3 d

231Th1.06 d

230Ac2.03 min

229Ra4 min

232Th1.41E+10 y

231Ac7.5 min

230Ra1.55 h

231Pa32800 y

230Th75400 y

229Ac1.04 h

228Ra5.75 y

230Pa17.4 d

229Th7880 y

228Ac6.14 h

227Ra42.2 min

229Pa1.5 d

228Th1.91 y

227Ac21.8 y

226Ra1600 y

228Pa22 h

227Th18.7 d

226Ac1.23 d

225Ra14.9 d

227Pa38.3 min

226Th30.6 min

225Ac10 d

224Ra3.66 d

226Pa1.8 min

225Th8.7 min

224Ac2.9 h

223Ra11.4 d

Ra-223

232Th (p, p5n) 227Th232Th (p, 6n) 227Pa (38 min, EC, 15%) → 227Th

227Th (18.7 d, α, 100%) → 223Ra

233Pa*232Pa1.3 d

231Th1.06 d

230Ac2.03 min

229Ra4 min

232Th1.41E+10 y

231Ac7.5 min

230Ra1.55 h

231Pa32800 y

230Th75400 y

229Ac1.04 h

228Ra5.75 y

230Pa17.4 d

229Th7880 y

228Ac6.14 h

227Ra42.2 min

229Pa1.5 d

228Th1.91 y

227Ac21.8 y

226Ra1600 y

228Pa22 h

227Th18.7 d

226Ac1.23 d

225Ra14.9 d

227Pa38.3 min

226Th30.6 min

225Ac10 d

224Ra3.66 d

226Pa1.8 min

225Th8.7 min

224Ac2.9 h

223Ra11.4 d

232Th (p, x) 225Ac232Th (p, p7n) 225Th (8 min, EC, 10%) → 225Ac232Th (p, 4n) 229Pa (1.4 d, α, 0.48%) → 225Ac232Th (p, x) 225Ra (14.8 d, β-, 100%) → 225Ac

Ac-225

Impurities 227Ac (T1/2 = 21,77 y)

Impurities 224Ra (T1/2 = 3,66 y) and225Ra (T1/2 = 14,9 y)

0

25

50

75

100

20 40 60 80 100 120 1400.00

0.05

0.10

0.15

0.20

224 R

a Im

pur

ity, %

225 A

c Yi

eld (m

Ci/µA·h

)

224Ra Impurity

223Ra Yield

223 R

a Yi

eld (m

Ci/µA·h

)

0.0

0.3

0.6

0.9

20 40 60 80 100 120 1400.00

0.04

0.08

0.12

227 A

c Im

pur

ity, %

227Ac Impurity

225Ac Yield

Energy(proton, MeV)

Separation and obstacles

Gamma-spectrum of irradiated thorium target

Over 80 radionuclides - products of nuclear reactions of fission and

spallation were identified: 230,233Pa, 227,228Th, 225,227Ac, 99Mo, 131m,132Te,

115Cd, 126,127Sb, 95,97Zr, 95,96Nb, 140La, 140Ba, 130,131,133I, 141,144Ce, 136Cs, 14

7Nd, 223Ra, 103Ru, 148mPm, 105Rh et al.

Separation and obstacles (Dr. Aleksandr N. Vasiliev From INR)

• High yield of the products - 225Ac and 223Ra (not l

ess than 85%); can be acquired

• Purification from a number of various radionuclide

s; can be possible

• High chemical and radiochemical purity of the pro

ducts; can be achieved

• The minimum number of steps for the separation

• Scalability for processing in hot cells.

Separation and obstacles (Dr. Aleksandr N. Vasiliev From INR)

Target irradiation parameters :Proton energy range 120-60 MeVTarget mass up to 80 gBeam current 100 µAIrradiation time 10 days Decay after EOB 5 days

production potential of 225Ac and 223Ra productionat INR RAS (Moscow):

225Ac 2.6 Ci 227Ac impurity 0.1 %

223Ra (DGA eluate) 3.8 Ci impurities: 224Ra (3.7 d) 19 %

225Ra (14.9 d) 0.78 %

223Ra (from org. phase) 3.3 Ci impurities: 224Ra (3.7 d) 25 %

Separation and obstacles (Dr. Aleksandr N. Vasiliev From INR)

Current status of producing countries

World production of Ac-225[1], GBq (мCi),

[1] A. Morgenstern et al (2011). "Targeted Alpha Therapy with 213Bi." Current Radiopharmaceuticals 4: 295-305.[2] Report of Technical Meeting on "Alpha emitting radionuclides and radiopharmaceuticals for therapy“ which held June, 24−28, 2013 IAEA Headquarters, Vienna, Austria

JRC ITU (EU) ORNL (USA) IPPE (Russia)Stock amount 1,7 (45,6) 5,55 (150) 5,55 (150)

Max. Annual quantity of producing Ac-225

13 (350) 22,2 (600) 26,6 (720)

Max. batch size 1,3 (35) 2,2 (60) 1,85 (50)

Total: about 63 GBq (1,7 Ci) 225Ас 100-200 patients

Alternatives

1. Purification Ac-225 2. Generator

• Production of At-211 is more easier and cheaper

(10 doller/mCi in Duke Univ.)

• Similar to I-123 production technique

Alternatives

At-211 (7.2 h) Curr Radiopharm. 2011 Jul; 4(3): 177–185.

Possible nuclear reaction

209Bi (α, 2n) 211At (A)

209Bi (α, 3n) 210At (B)

Technical Reports Series

Number 468, International

Atomic Energy Agency:

Vienna, 2009, pp. 33-40 with

permission from the IAEA.

At-211 (7.2 h) Curr Radiopharm. 2011 Jul; 4(3): 177–185.

Potential At-211 production site in EU

At-211 (7.2 h) Curr Radiopharm. 2011 Jul; 4(3): 177–185.

Potential At-211 production site in ASIA

At-211 (7.2 h) Curr Radiopharm. 2011 Jul; 4(3): 177–185.

Potential At-211 production site in America

Lu-177 (ββββ- particle)

• Lutetium-177 does β- decay

• 0.497 MeV beta particle (max 2.76mm)

• Emission of a 208 keV gamma photon (11 %)

allows imaging for evaluation of localization and

biokinetics, and for targeting applications

• Even modest thermal neutron flux (e.g. > 1 x

1014) can produce Lu-177

Conclusion

• Alpha (at least beta) particle is necessary

• Alpha particle should be developed ASAP

• Related radiopharmaceutical research should be

preceded

• More practical research is necessary, directly

applicable for therapy