Radiolabeling of Small Molecules by fjzhangxiaoquan


									       International Atomic Energy Agency

      Therapeutic Radionuclides:
Options, Production and Radiochemical

                   M.R.A. Pillai
  Industrial Applications and Chemistry Section
           Goals of Presentation

• Review of radioisotopes requirements for
• Review of the therapeutic radionuclides
• Important therapeutic radionuclides
• Production of a few of them

                               International Atomic Energy Agency
              Radionuclide Therapy

• Hyper thyroidism
• Treatment of cancer
• Bone pain palliation
• Radiosynovectoy for Rheumatoid arthritis
• Radionuclide therapy started with 131I and it
    continue to occupy a role in nuclear medicine
•   131I is the best magic bullet one can ever

    perceive with >33% uptake in the thyroid

                                  International Atomic Energy Agency
                Why 131I is widely used?

• 131I can be prepared in medium flux reactors in
    adequate quantities
•   The isotope is of high specific activity due to
    the production route followed; (n,f) or (n,g)
    followed by b- decay
•   The Worldwide use of 131I is feasible
    • Logistics of production
    • Long half life enables the movement of the isotope
        around the globe
    •   High specific activity
    •   Affordability

                                      International Atomic Energy Agency
        Radionuclide therapy beyond 131I

• 131I will continue to be the best option for CA
•   Despite the several advantages of 131I, it has
    limited use for development of
    radiopharmaceuticals for targeted therapy of
•   The large percentage of gammas in the case of
    131I are not ideal for targeted therapy

•   Thus there is a need for other isotopes like 131I
    for therapy diseases other than that of the
                                   International Atomic Energy Agency
Review of current diagnostic investigations

• About 30-35 million diagnostic
    investigations are done per year the
    world over
•   99mTc is the major diagnostic radionculide

•   Substantial part of it accounts for
    cardiology and bone
•   Several other conventional nuclear
    medicine studies are done with 99mTc

                              International Atomic Energy Agency
Can we find a match equivalent isotope to
           99mTc for therapy?

• Targeted therapy using radionuclides are
  taking a leap in cancer therapy
• If 1 % of the diagnostic investigations need
    radionuclide therapy, ~ 300,000-350,000
    therapy doses are needed per year
•   China reported about 200,000 radionuclide
    therapy (Damen Chen)
•   ~ 150-500 mCi per patient is needed
•   Modest estimate is that several million Curies
    of therapeutic radionuclides are needed
•   If that is the case, what are our options?
•   Which are the most favourable isotopes?

                                  International Atomic Energy Agency
            Radionuclide therapy

• High linear energy transfer (LET) is
    essential for radionuclide therapy
•   Radionuclide therapy can be done with
    alpha or beta emitting radionuclides

                             International Atomic Energy Agency
     Isotopes decaying with alpha emission
•   211At,149Tb, 223Ra, 213Bi, 225Ac

•   High linear energy transfer (LET)
•   High levels of cytotoxicity
•   Most of the isotopes are difficult to produce
•   A few clinical trials are currently going on
•   Not expected to be widely available for the immediate future

Zalutsky M.R., Pozzi O.R., Vaidyanathan G., ’Targeted radionuclide therapy using alpha
    particle emitting radionuclides’. Proc. International Symposium on Trends in
    radiopharmceuticals (ISTR 2005). 25-38, IAEA, Vienna, 2007.

                                                             International Atomic Energy Agency
As of today the choice of mass scale
radionuclide therapy is beta emitting

                         International Atomic Energy Agency
    Selection of a Therapeutic Radionuclide

• Mode of Decay- b- is the choice
• Energy of the b- particles (Depends on
    the application, but low energy preferred)
•   Availability of gamma photons
•   High specific activity
•   Half life- Advantageous to have a long
    half life (few days)

                               International Atomic Energy Agency
          b- Emitting Radionuclides for Therapy

Short Range           Medium Range        Long Range

Isotope    T1/2 (d)   Isotope   T1/2 (d) Isotope T1/2 (d)
 199Au        3.1      153Sm      1.9      165Dy               0.1
 169Er        9.3      143Pr     13.6         89Sr             50
 175Yb        4.2      170Tm    128.6        32P               14
 177Lu        6.7      198Au      2.7      166Ho               1.1
 67Cu         2.6      111Ag      7.5      188Re               0.7
 105Rh        1.5      109Pd      0.5       142Pr              0.8
  47Sc        3.4      186Re      3.8        90Y               2.7
  131I        8.0
                                        International Atomic Energy Agency
Range of Electrons in Soft Tissue
    (Maximum Beta Energy)

                                  Re-186    P-32
Range (mm)

               0.1                          Re-188
                               Sn-117m (CE)
             0.001   Augers – Intracellular – Pt-195m
                     Alphas– 5-8 Cell Diameters – Th-229

                        0.1 0.2         1   2         10
                               Electron Energy (MeV)

                                                   International Atomic Energy Agency
        Availability is the key issue
• Production
  • Reactor or Generator produced
• High production yield
• Easy radiochemical processing
• Established generator technology
• Transportation
• What are the isotopes that can be
 produced easily?

                              International Atomic Energy Agency
             Isotopes for therapy

• Reactor produced
  • 177Lu, 153Sm, 188/186Re, 166Ho, 161Tb, 170Tm
• Generator Produced
  • 90Y and 188Re
  Generator produced isotopes are not covered
                 in this lecture

                                   International Atomic Energy Agency

       International Atomic Energy Agency
      Advantages of 177Lu for Therapy

• Beta Energy - β max = 0.497 MeV –  Low tissue
  penetration – advantages for targeting
  microstatic disease
• Imaging - 111 keV gamma (6.7%) and 208 keV
  (10%) useful for imaging
• Half-life – 6.7 days - major advantage - permits
  broad distribution
• Chemistry - + 3 metal
• Production - can be produced with high
  specific activity
                                 International Atomic Energy Agency

•   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)
•   Chelates well with N,O,P,S donor ligands such as
    DOTA, Phosphonates
•   Very high stability of 8/9 coordinated chelates
        Metal       Stability Const. (M-1) with DTPA
        Lu                     2.51x1022
        Y                      1.12 x1022
        Sm                     6.84 x1021
                                              International Atomic Energy Agency
             177Lu    is the ‘metallic iodine’
  Characteristics               Iodine-131                     Lu-177

Half life              8.02 d                     6.73 d
Beta energy (%)        606 keV (89%)              497 keV (78.6%),
                                                  384 keV (9.1%),
                                                  176 keV (12.2%)
Gamma energy (%)       364 keV (81%)              113 keV (6.4%)
                                                  208 keV (11%)
Production- Reactor    235U (n,f)                 176Lu(n,g)177Lu
                       131Te(n,g)131Te to 131I    176Yb(n,g)177Yb    to 177Lu

Specific activity      High ~ 20% isotopic        > 20% and up to 100%
                            abundance                 isotopic abundance
                       129I and 127I is present

Chemistry              Halogen                    Metal chemistry (+3)

Use (main)             Targeted therapy           Targeted therapy
                       (mainly thyroid)           (other than thyroid)

                                                  International Atomic Energy Agency
           Application of 177Lu

• Bone pain palliation
• Targeted therapy
• Small and medium joint Synoviorthesis

                           International Atomic Energy Agency
               Lutetium-177 Is produced by irradiation of
                      Enriched Lu-176 or Yb-176

                            Direct Route
                  Lu-176       n, g        Lu-177 +          Lu-177m
                         σ = 2100 barn   6.73 days           160 days
                                                 Indirect Route
                               Beta Decay          Beta Decay
                             Route Provides      Improved/optimized
                            Carrier-Free route   separation required
                                                 Not preferred

                  Yb-176       n, g         Yb-177
                           σ = 2.85 barn   1.9 hours

                                                  International Atomic Energy Agency
ORNL 2000-06539a/rra
                Production of 177Lu
• Irradiation
  •   Natural (2.6% 176Lu)
  •   Enriched (60-80% 176Lu)
  •   5-7 d (careful optimization needed)
• Chemical processing
  •   Dissolution in 0.1 M HCl to obtain LuCl3 used for labeling
• Specific Activity
  • Upto 70 Ci/mg reported
• Radionuclidic purity
  •   by g ray spectrometry
  •   Only contamination 177mLu
  •   RN purity >99.99%, 5.5 kBq 177mLu/ 37 MBq 177Lu (150 nCi/

                                             International Atomic Energy Agency
 Production of Lutetium-177 from
“Direct” Production of Lutetium-177
   Enriched Lutetium-176 Target
     from Lutetium-176 Target
                         High thermal neutron cross section – σ = 2100 barns
                          High Flux Allows near Theoretical Specific Activity
                             2 x 1015 n cm-2 s-1 (thermal)                 177Lu

                             1 x 1014 n cm-2 s-1 (epithermal)
                    60                                            Specific Activity = 109 Ci/mg
                                              ORNL HFIR

                                                                 30% of Theoretical
                                                                 HANARO - MURR
                    40                                           4-5 x 1014 n cm-2 s-1 (thermal)
 Activity (Ci/mg)

                                                                 1 x 1012 n cm-2 s-1 (epithermal)

                                     1 x 1014 n cm-2 s-1 (thermal)
                    10               1 x 1012 n cm-2 s-1 (epithermal)

                         0           5            10       15       20                              25
                                            Irradiation Time (Days)
                                                                            International Atomic Energy Agency
                                                                                                              Gamma-ray spectrum of 177Lu

                                                              208 keV ( Lu)
                                                                                                                                     Radionuclidic purity of
                                             113 keV ( Lu)


                                                                                                                                       177Luachievable is
                                      72 keV( Lu)


                                                                                                                                     The average level of
                                                                              250 keV( Lu)
                                                                                              321 keV( Lu)


Net counts (log scale)

                                                                                                                                       radionuclidic impurity
                           100                                                                                                         burden in 177Lu due to
                                                                                                                                       177mLu found to be 5.5

                                                                                                                                       kBq of 177mLu / 37 MBq
                                 0                                                                             1000
                                                                                                             Channel number
                                                                                                                                       of 177Lu (150 nCi /mCi)
                                                                                                                                       at EOB

                                                                                                                                          International Atomic Energy Agency
        Specific activity of 177Lu formed
               by direct method
• Direct (n,g) irradiation can give >20 Ci/mg
    than in many of the medium-high flux
    research reactors which is adequate for
    radionuclide therapy
•   The maximum achievable specific activity
    of 131I is ~ 20 Ci/mg
•   By carefully optimizing reactor irradiation
    conditions up to 40 Ci/mg has been
    obtained at 1.8x1014 n/cm2.sec
                               International Atomic Energy Agency
                 177Lu   from 176Yb
• Also produced by (n,g) activation followed by
    beta decay
•   176Yb (n,g) 177Yb    177Lu

•   Low cross section: 2.4 barns
•   Enriched 176Yb needed
•   Theoretical specific activity 109 Ci/mg
•   Good radiochemical separation is needed
•   Lanthanide separation is difficult but methods
    are reported/patented
•   Electrochemical separation is being developed
    for this

                                  International Atomic Energy Agency
                177Lu   from 176Yb
• 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
•   177mLu contamination will be less by this

    method, but it is not a real issue (?)
                                International Atomic Energy Agency
               177Lu-   Current status

• 177Lu has emerged as a major therapeutic
•   Several clinical studies are currently going on
    with 177Lu
•   Major suppliers are offering 177Lu
•   177Lu-DOTATATE is already in use in several

    countries for treatment of neuroendocrine
•   IAEA has sponsored a multicentric clinical trial
    of 177Lu-EDTMP
                                   International Atomic Energy Agency
Why should 177Lu be cheap?

                   International Atomic Energy Agency
             Activity Produced A         = NFs
                         89Sr     99Mo          153Sm              177Lu

Cross section           0.0058    0.13            206               2100
Activity produced       0.0035     7.7           9150             39000

•   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

                                         International Atomic Energy Agency
    Who are the potential producers of 177Lu

• 177Lu for bone pain palliation can be
    prepared in reactors having >5x1013
•   177Lu for peptide and antibody labelling

    can be prepared in reactors having >1-
    2x1014 n.cm2.sec
•   India is currently making 177Lu
•   The new HFRR in China can be a good
    source for 177Lu in the region

                               International Atomic Energy Agency
        What should be the cost of 177Lu

• 99Mo available at ~300 USD per Ci (37
•   99Mo is fission produced needing

    elaborate radiochemical processing
•   Needs enriched 235U
•   131I is prepared either from fission of 235U

    or by (n,g) activation of 130Te
•   131I needs elaborate radiochemical


                                International Atomic Energy Agency
        What should be the cost of 177Lu

• 177Lu can be directly produced in large
•   Enriched target is available, not needed in large
    amounts and is not very expensive
•   The cost of 177Lu should not exceed that of
    99Mo or 131I

•   Current prices of 177Lu are commercially driven
•   More production sites, large use and
    competition can bring the cost down

                                   International Atomic Energy Agency
        IAEA efforts are showing fruition

• IAEA CRP on Comparative evaluation of
    therapeutic radiopharmaceutical explored the
    possibility of making 177Lu
•   177Lu is prepared in several countries

•   177Lu-EDTMP clinical trial is successfully going
    on in many countries
•   177Lu-DOTATE is benefitting patients in many
•   New national projects are submitted to IAEA
•   The output of the IAEA CRP will be the first
    book on ‘Lutetium-177 radiopharmaceuticals’
                                   International Atomic Energy Agency
Growth of 177Lu Literature




 Number of publications on






                                  1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
                                                         Year of publications
                                                                                             upto 10.09.2009

                                                                                         International Atomic Energy Agency
                                          177Lu                in different journals

                                          J. Nucl. Med.
                                      Nucl. Med. Biol.
                        Cancer Biother. Radiopharm.
                          Eur. J. Nucl. Med. mol. Img.
                                  Bioconjugate Chem.
                                     Clin. Cancer Res.
Name of the Journals

                                            Cancer Res.
                       J. Label. Compd. Radiopharm.
                                        Phy. Med. Biol.
                                          Int. J. Cancer
                                         J. Clin. Oncol.
                                 Nucl. Med. Commun.
                       Quart. J. Nucl. Med. Mol. Img.
                                  Bioorg. Med. Chem.
                            Bioorg. Med. Chem. Lett.
                                  Curr. Pharm. Design
                                Endocr.-Relat. Cancer

                                                           0     5   10        15        20         25       30         35
                                                                     No. of articles on 177Lu published

                                                                                                               Updated on 10.09.2009

                                                                                              International Atomic Energy Agency
Other reactor produced therapeutic
     radionuclides of interest

                       International Atomic Energy Agency

• T1/2 17 h; Ebmax 2.12 MeV; 155 keV gamma
    energy suitable for imaging
•   187Re(n,g)188Re; low specific activity

•   Group VIIb element and hence mimics Tc
•   Forms an ideal diagnostic-therapeutic pair with

•   Direct (n,g) produced 188Re is not preferred due
    to low specific activity, contamination with
    186Re and short half life

•   188W/188Re generator is preferred

•   Useful for bone pain palliation
                                   International Atomic Energy Agency

• Half life 64 h
• Low energy 0.81 MeV (Ebmax)
• 28% gamma can be used for imaging
• 186Re(n,g)186Re
• Activation cross section 106 barns
• Natural abundance 26.7%
• Enriched target 185Re is available
• Atom% 1.76: Low specific activity
• Useful for bone pain palliation studies

                                 International Atomic Energy Agency

• Useful for bone pain palliation studies
• Less bone marrow dose
• Useful for medium joint
•   Specific activity is low for receptor
    specific RPS and monoclonal antibodies
•   64 h half life is suitable for shipping

                             International Atomic Energy Agency

•   T1/2 50.53 d; Ebmax 1.49 MeV
•   Successfully used as a bone pain palliation agent
•   88Sr(n,g)89Sr

•   Very poor cross section (0.0058 barns)
•   Natural abundance 82.6%, hence using enriched target
    does not improve the specific activity
•   High flux reactor essential to produce reasonable
•   The product from low and medium flux reactors will not
    be suitable for therapeutic studies, due to possible
    chemical toxicity
•   Suitable for bone pain palliation

                                      International Atomic Energy Agency

• T1/2 47 h; Ebmax 0.81 MeV
• 152Sm(n,g)153Sm
• Natural abundance 26.7%
• Activation cross section of 206 barns
• Enriched target 152Sm is available
• Useful for bone pain palliation studies
• Less bone marrow dose
• Useful for medium joint radiosynoviorthesis
• Specific activity is low for receptor specific
  RPS and monoclonal antibodies

                                 International Atomic Energy Agency

• T1/2 26.9 h; Ebmax 1.85 MeV
• 165Ho(n,g)166Ho
• Activation cross section 66 barns
• Mononuclidic element, 100% isotopic
• 6.4% gamma abundance, can be used for
  mapping the radiopharmaceutical in vivo
• Useful for bone pain palliation studies, high
  bone marrow dose
• Useful for large joint radiosynoviorthesis
• Specific activity is too low for receptor specific
  RPS and monoclonal antibodies
                                  International Atomic Energy Agency
Why not 170Tm for bone pain palliation?

                          International Atomic Energy Agency

     170Tm-EDTMP:     A potential cost effective
    alternative to 89SrCl2 for bone pain palliation
T.Das, S. Chakraborty, H.D.Sarma, P. Tandon, S.Banerjee,
                M.Venkatesh, M.R.A. Pillai
    Nuclear Medicine and Biology, 36,561-568, 2009.

                                    International Atomic Energy Agency
                             170Tm          and 89Sr
Parameters                           89Sr                               170Tm

Half-life                        50.53 d                               128.6 d
Maximum b- energy             1496.6 KeV                              968 KeV
Principle g (% abun.)          Negligible                       84.3 keV (3.26%)
Tissue penetration              ~7.5 mm                                 ~5 mm
Production routes             88Sr(n,g) 89Sr                    169Tm    (n,g) 170Tm
                             89Y(n,p)89Sr *1

                             0.0058 b                                 103 b
Target (% abun.)             88Sr    (82.58%)                      169Tm    (100%)
Need for enrichment     Yes, to avoid RN impurity              No, Mono-nuclidic
Specific activity        1.34 GBq/g (35 mCi/g)          6.08 TBq/g (164 Ci/g)

                                                       International Atomic Energy Agency
                   Biodistribution pattern of 170Tm-EDTMP
                                 in Wistar rats

  Organ/Tissue                      %Injected activity (%IA)
                          3h                   1d                         3d
Blood                  0.150.05            0.000.00                 0.000.00
Liver                  0.140.01            0.140.01                 0.160.01
GIT                    2.410.02            1.830.44                 1.050.64
Kidney                 0.300.02            0.280.04                 0.360.13
Stomach                0.860.16            0.470.22                 0.060.06
Heart                  0.020.01            0.010.00                 0.000.00
Lungs                  0.050.01            0.020.01                 0.000.00
Skeleton               51.653.78          55.767.25                54.567.47
Muscle                 2.820.32            0.220.06                 0.000.00
Spleen                 0.020.01            0.000.00                 0.000.00
Excretion              36.912.77          41.307.43                43.818.03
Skeleton / Blood         344.33             Very high                 Very high
Skeleton /               18.32                    International Atomic Very high
                                             253.45                    Energy Agency
           Imaging studies in Wistar rats

3 h post-injection                45 d post-injection
                                      International Atomic Energy Agency

• Stand alone therapeutic agent instead of

• 153Sm gives fast but short term pain relief
• 89Sr gives delayed but long term effects
• Combination therapy with 153Sm or 177Lu-
    EDTMP to give both short and long term
•   Add 5 mCi of 170Tm and 70 mCi of 177Lu to
    an EDTMP kit to make the patient dose

                              International Atomic Energy Agency
          The main objection for 170Tm
• Can we use an isotope with T1/2 129 days?
• T1/2 of the isotopes used for bone pain
    palliation varies from 17 h (188Re) to 50 days,
    why not extent it to 129 days?
•   What are the safety implications?
•   It may need only 4-5 mCi of 170Tm-EDTMP
•   If 170Tm-EDTMP becomes an approved product,
    bone pain palliation can travel to all parts of the
•   Outpatient therapy could be developed
•   Who will push this?
                                    International Atomic Energy Agency
• Large quantities of radioisotopes are needed for
•   The choice of the isotope will depend on the type
    of therapy
•   Local production or easy transportation is
•   Long lived reactor produced or generator produced
    isotopes are preferred
•   High specific activity is important for targeted
    therapy, there may be limited sources
•   Low specific activity isotopes can be used for bone
    pain palliation and radiosynovectomy

                                    International Atomic Energy Agency
• 177Lu holds great promise for wider application
• Large quantities of high specific activity 177Lu can
    be prepared by irradiating enriched targets
•   Medium Flux reactors can produce 177Lu for bone
    pain palliation
•   High Flux reactors can be used for 177Lu for
    targeted therapy
•   Exotic thinking to bring new radioisotopes is
•   Regional cooperation is important to enhance
    targeted therapy
•   Trans boundary assistance…
                                    International Atomic Energy Agency
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