technetium: mo/ tc “generators” and production of tc...

Technetium: 99Mo/99mTc “generators”and production of Tc radiotracers

*Board of Interdivisional Group of Radiochemistry, GIR

Italian Society of Chemistry, SCI

*Mauro L. Bonardi and Flavia GroppiRadiochemistry Laboratory, LASA

Universita’ degli Studi and INFN, Milano, Italy

Collaborations: JRC-Ispra-EC, IAEA-NDS, ATOMKI-Debrecen-HU,Beer Sheva-Israel, INR-Russia, NIST-USA, LANL-USA,

TRIUMF-CA, ORNL-USA, iThemba LABS-SA

http://wwwGIR.mi.infn.it

*EuCheMS-Division NRC, ANS-IC

[email protected] [email protected]

International Union of Pureand Applied Chemistry

mailto:[email protected]:[email protected]

Main steps in accelerator (or reactor) production of a labelled compound (e.g. radiopharmaceutical)

The Quality Control (QC) and God Manufacturing Practice (GMP) are mandatory for each step of the procedure

In a selected number of cases, it is possible to avoid the radiochemical ich happens in target itself: recoil labelling with hot atomsprocessing step, wh

99Mo

87.6

%

36Kr 37Rb 38Sr 39Y 40Zr 41Nb 42Mo 43Tc 44RuISOBAR-99

99mTc

35 36 37 38 39 40 41 42 43 44 45

10-1210-1110-1010-910-810-710-610-510-410-310-210-1100101

RbNb

YSrZr

Kr

inde

pend

ent f

issi

on y

ield

(%)

atomic number , Z

Tc

Mo

Independent Fission Yields (%) of thermal neutrons on U-235

isobar-99 comulative yield = 6.161% gaussian model

β − decay

Z.B. ALFASSI, M.L. BONARDI, J.J.M. De GOEIJ, F. GROPPI, On the “carrier-free” nature of 99mTc, Appl. Radiat. Isot., 63 (1) (2005) 37-40.

Simplified decay scheme of isobar-99 and Mo-Tc “generator”The 99mTc is never a carrier-free radionuclide due to the unavoidable presence of the long-lived 99gTc isotopic carrier

W.C. ECKELMAN, M. BONARDI, W.A. VOLKERT, True radiotracers: are we approaching theoretical specific activity with Tc-99m and I-123?, Nucl. Med. Biol., 35 (5) (2008) 523-527.

Present WorldDemand

450.000 GBq/week12.000 GCi/week

[email protected]@mi.infn.it


• Classical Nuclear Reactor Methods for production of 99Mo 99mTc “generator”

*(HEU 99 %) U-235 (n,fiss) Mo-99 thermal neutrons 36.10 barn # (σfiss = 586 b)(liquid LEU 20 %) U-235 (n,fiss) Mo-99 thermal neutrons 7.22 barn #

#normalized to 6.161 barn of isobar 99 on 235U

*Mo-98 (nat 9.63 %) (n,γ) Mo-99 thermal neutrons 0.14 barn

• New Possibilities via 99Mo 99mTc “generator”*Mo-100 (nat 9.63 %) (n,2n) Mo-99 neutrons 6 - 17 MeV 1.5 barn $

$ Yasuki NAGAI, Yuichi HATSUKAWA, Production of 99Mo for Nuclear Medicine by 100Mo(n,2n)99Mo, J. Phys. Soc. Japan Letter, 78 (3) (2009)

033201*Mo-100 (γ,n) Mo-99 $GDR 10–30 MeV photons (bremstrahlung, Thomson)*Mo-100 (p,pn) Mo-99 15 – 64 MeV protons 158 mbarn (max)*Mo-98 (n,γ) Mo-99 %ARC thermal-epi neutrons from protons 1 GeV, 1 mA*[Mo-98]complex Szilard-Chalmers Mo-99 thermal-epithermal neutrons > 0.14 barnU-nat (p,fiss) Mo-99 70 MeV protons about 30-50 mbarnU-nat (d,fiss) Mo-99 fast deuterons U-nat (γ,fiss) Mo-99 10 – 30 MeV fast photons (bremstrahlung, Thomson)

*Zr-96 (nat 6.8 %) (α,n) Mo-99 15 – 35 MeV alphas

• Direct production of 99mTc from molybdenum target ( without “generator )*Mo-100 (nat 9.63 %) (p,2n) Tc-99m (+Tc-99g) 12 – 22 MeV 200 mbarn (max)*Mo-98 (p,γ) Tc-99m (+Tc-99g) 30 – 50 MeV 130 mbarn (max)

*Mo-98 (d,n) Tc-99m (+Tc-99g) 10 – 35 MeV

* high enriched target $ Giant Dipole Resonance % Adiabatic Resonance Crossing

Cross-sections of neutrons on 98Mo

1 / v law

several resonances

Radiative neutron capture cross section of 98Mo(n,γ)99Mo , (the epithermal contribution could be substantial)

epithermal

thermal neutrons

0.14 barn

0.02

5 eV

fiss CB for protonson 238U = 12.3 MeV

10 MeV p

100 MeV p

Fission of 238U with 70 MeV protonsthe σ of isobar—99 is about 30-50 mbarn

In radiochemistry, the short half-life must gain a radiochemical yield (RCY) larger than the chemical yield (CY) of conventional chemistry. The blue line represent in

semilog scale the decay of radionuclide during the radiochemical steps.EOP: End Of radiochemical Processing

The “generators” : 99Mo 99mTc

The classical and widespread 99Mo 99mTc generator is based on a small radiochromatographic column (normally of stainless steel) filled with a few cm3 of acidic alumina (AAO or acidic Al2O3) and the single charged aqua-anion TcO4- is eluted with a physiological saline solution (NaCl 0.9 %), while the double charged anion MoO42- is strongly retained onto the column (see next slides).

Other generators based on different filling materials:• gel of zyrconium molybdate, for large volume samples starting from either liquid LEU

or highly enriched 98Mo targets

• performances of nanoparticellar zyrconia vs. alumina

• PZC: solid support of nanocomposites of polyzirconyl anion exchanger

• PTCs: different kinds of Phase Transfer Catalysts (enhance velocity of either nucleofilic substitution or electrofilic addition/substitution smaller reagent and solvent volumes), for low-medium activity

• DOWEX-1x8 or AG1x8 strong anion exchanger, for low-medium activity (radiation damage due to the organic lattice)

Electrochemical generator (similar to 90Sr/90Y one, developed in India)

13

Present World

Demand450 TBq/week12 TCi/week

2sterilysing

filter

TcO

4-el

uted

Mo

2-ad

sorb

ed30

cm

4

15 cm

TcO

4-el

uted

100

% ?

Mo 4

2-ad

sorb

ed10

0 %

?

15 cm

30 c

m

15 cmPresent World

Demand

450 TBq/week12 TCi/week

2

3

sterilysingfiltern

o M

o

brea

kthr

ough

!

X

Elution profile of 99mTc from a 99Mo “generator”(the elution is carried out as a rule every 24 h)

99Mo

99mTc

87.6

%

Tmax = 22.83 h withdecay branching

of 100 %

0 24 48 72 96 120

10

100

time (days)

99M

o an

d 99

mTc

act

ivity

(%)

time (hours)

0 1 2 3 4 5

elut

ion

6

elut

ion

5elut

ion

3

elut

ion

2

elut

ion

1

RCY of elutions 100 %

elut

ion

4

decay branching100 % (black dots)

realbranching87.6 %

Taken from Dewi M. Lewis (GE) and Natesan Ramamoorthy, IAEA, Vienna , WORKSHOP “PHYSICS FOR HEALTH IN EUROPE”, CERN 02 - 04 Feb 2010

1 Accelerator or Research Reactor

facility for target irradiation

The accelerators are normally cyclotrons or linac (light ions and electrons for intense

photon beams)

2 Radiochemical Processing in a

series of Hot-Cells and master-slave

manipulators

3 Partitioning of bulk activity after QC under GMP

rules and restrictions

Schematics of main stepsin commercial production

of radionuclides and radiopharmaceuticals



Hot Cell facility for radionuclide processing at LANLEach cell dedicated to 1 different radionuclide or radiopharmaceutical

Master-Slave manipulators

Pb glass windows

Manip Hand Hood

Dis

pens

ary

Cel

lWarm Corridorfor maintenance

Cell1

Cell2

Cell3

Cell4

Cell5

Cell6

Cell7

Cell8

Cell9

Cell10

Cell11

Cell12

Cell13

Foye

r

TrainMaintRoom

Dis

solv

ing

Ben

ch

train

railw

ay

Master Cell

Train for activity

distribution

M-S

man

ipul

ator

s

Mauro Bonardi, Claudio Birattari, FlaviaGroppi, Enrico Sabbioni, Thin-target excitation functions, cross-sections and optimised thick-target yields for natMo(p,xn)94g,95m,95g,96(m+g)Tc nuclear reactions induced by protons from threshold up to 44 MeV. No Carrier Added radiochemical separation and quality control, Appl. Radiat. Isot., 57 (5) (2002) 617-635.

Other radionuclides of technetiumproduced in a proton cyclotron via

Mo(p,xn) reactions for research purposes (Milano and Ispra 1982 – 2004)

• Claudio Birattari, Mauro Bonardi, Marco Castiglioni, J. Edel, Monica Gattinoni, F. Mousty, Enrico Sabbioni, Gamma-emitting technetium radiotracers production for waste disposal studies at Milan AVF Cyclotron,Report INFN, INFN/TC-84/24, Frascati, Roma, 1984

• Andrea Marchi, Licia Uccelli, Luciano Magon, Mauro Bonardi, Mario Gallorini, Flavia Groppi, Sabrina Saponaro,

Technetium complexes with ligands of pharmacological interest, J. Radioanal. Nucl. Chem., 195 (1995) 237-242.• Mauro Bonardi e Flavia Groppi, Masurio-99m, Masurio-99, Renio-186g, Renio-188,: Radioelementi chimici isomorfi, ma

con attività specifica e proprietà chimico-fisiche differenti. Storia e produzione di radiotraccianti. Metodiche di produzione e controllo di qualità, Rapporto INFN/TC-01/04, Frascati, Roma, 2001

0 5 10 15 20 25 30 35 40 450

2

4

6

8

10

12

14

16

18

20

22

24 94gTc 95gTc

95mTc*103

96(g+m)Tc

Thin

Tar

get Y

ield

(GB

q/C

MeV

)

Proton Energy (MeV)



Ciclotrone 70 MeV

[email protected] and [email protected]

IUPAC

Technetium: 99Mo/99mTc “generators” and production of Tc radiotracersSimplified decay scheme of isobar-99 and Mo-Tc “generator”The 99mTc is never a carrier-free radionuclide due to the unavoidaRadiative neutron capture cross section of 98Mo(n,g)99Mo, (the epithermal contribution could be substantial)Fission of 238U with 70 MeV protons the s of isobar—99 is about 30-50 mbarnThe “generators” : 99Mo 99mTcElution profile of 99mTc from a 99Mo “generator”(the elution is carried out as a rule every 24 h)Hot Cell facility for radionuclide processing at LANLMauro Bonardi, Claudio Birattari, Flavia Groppi, Enrico Sabbioni, Thin-target excitation functions, cross-sections and optimi

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