A brief presentation on ligands used for preparation of diagnostic and therapeutic radiopharmaceuticals

1. Madhava B Mallia
Radiopharmaceuticals Division
Radiochemistry and Isotope Group
BHABHA ATOMIC RESEARCH CENTRE
Trombay, Mumbai - 400 085, INDIA
E-Mail: madhavmb@gmail.com
Ligands for radiolabeling with
medically important radioisotopes
for diagnosis and therapy

2. +
Radioisotope Biomolecule Radiopharmaceutical
Radiopharmaceuticals
Molecules tagged with a radioisotope used for diagnosis or therapy of various
diseases or to evaluate function of various organs
3/18/2019 2
Radiolabeling

3. 3/18/2019 3
Radiolabeling techniques
Non-isotopic labeling
Radiolabeling with
metallic radioisotopes
Radiolabeling with
non-metallic radioisotopes
Lanthanide labeling Transition metal labeling
Isotopic labeling

4. Isotopic labelling
3/18/2019 4
Production of 123/131I-meta iodo benzyl guanidine
Use: Diagnosis/therapy of medullary carcinoma of thyroid, pheocromocytoma,
neuroblastoma etc

5. 3/18/2019 5
Isotopic radiolabelling
O
O
I
I
Lipiodol
O
O
I
I 123/131I-NaI
Sealed vial, high temperature
O
O
I
I*
Lipiodol Radiolabeled Lipiodol
Use: Effective, economically viable, agent for therapy of liver cancer

6. 3/18/2019 6
Non-isotopic radiolabelling: Labelling with non-metals
18F-FDG – [18F]Fluorodeoxyglucose: “Molecule of the Millineum”

7. 3/18/2019 7
Acetonitrile
K 18F is obtained from cyclotron
Use: Cancer diagnostic agent

8. 3/18/2019 8
Non-isotopic radiolabelling: Labelling with non-metals
Use: Diagnosis/therapy of medullary carcinoma of thyroid, pheocromocytoma,
neuroblastoma etc

9. • Radioiodination
3/18/2019 9
Non-isotopic radiolabelling: Labelling with non-metals
Electrophilic substitution reaction

10. 3/18/2019 10

11. 3/18/2019 11
Chloramine-T method: Ideal for radiolabeling
antibodies and biomolecules containing tyrosine
moiety

12. Bolton-Hunter Reagent: The prosthetic arm for
radioiodination
3/18/2019 12
Biomolecule
NH2

13. 3/18/2019 13
Bolton-Hunter Reagent: (Sulfosuccinimidyl-3(hydroxyphenyl) Propionate)
Biomolecule
NH2
+
Na I*
Chloramine-T

14. 3/18/2019 14
Non-isotopic radiolabelling: Labelling with metals
Most common Reducing agents:
• SnCl2
• NaBH4
MIBI – Methoxyisobutyl isonitrile 99mTc–sexta MIBI
Tetrofosmin 99mTc–Tetrofosmin
Isocyanide ligand
Trivalent phosphorus ligand
Myocardial perfusion imaging agents

15. 3/18/2019 15
EC – Ethylene dicystein 99mTc–EC
EC – Ethylene dicystein diester 99mTc–L, L - ECD
Renal imaging agent
Brain perfusion imaging agent
N2S2 type ligand

16. Radiolabeling using pre-formed metallic cores
3/18/2019 16
MIBI – Methoxyisobutyl isonitrile 99mTc–sexta MIBI
Conventional technetium-99m chemistry
Novel cores of technetium-99m

17. [99mTcN]2+ core
3/18/2019 17
SDH – Succinic dihydrazide X – labile ligand
+
Symmetric 99m TcN-complex

18. 3/18/2019 18
Diethyl dithiocarbamate 99m TcN-Diethyl dithiocarbamate complex
Symmetric 99m TcN-complex

19. Asymmetric radiolabeling with [99mTcN]2+ core
3/18/2019 19
Why?
Bulky biomolecules  Bulky complex
Poor pharmacokinetics

20. How?
3/18/2019 20
PNP - ligands

21. 3/18/2019 21

22. [99mTc(CO)3(H2O)]+ core
3/18/2019 22
K+

23. 3/18/2019 23
Tc
Y
CO
CO
Z
OC
X
Multiple possibilities
Tc
Y
CO
CO
Z
OC
X
Tc
Y
CO
CO
Z
OC
X

24. Controlling overall charge...
3/18/2019 24
99m
Tc
CO
OH2
OH2H2O
OC CO
+
Technetium99m-
tricarbonyl
triaqua core
H N
O
O H
O
H O
H N N H 2
H 2 N
H N N H 2
O
H O
9 9 m
T c
O C
O C
C O
N H
O
O
O
O
9 9 m
T c
O C
O C
C O
N H
O
O N H 2
9 9 m
T c
O C
O C
C O
N H
H 2 N N H 2
-1
0
+ 1

25. 3/18/2019 25
N N
N
O
O
99m
Tc
CO
OC CO
N N
N
OH
OH
+
70o
C, 30 min
pH = 8
-
CO
CO
OC
OH2H2O
OH2
+
99m
Tc
O
O O
O
N N
N
NH2
NH2
99m
Tc
CO
OC CO
N N
N
NH2
NH2
+
100o
C, 60 min
pH = 8
+
CO
CO
OC
OH2H2O
OH2
+
99m
Tc
IDA complex
DETA complex
N N
N
O
NH2
99m
Tc
CO
OC CO
N N
N
OH
NH2
+
100o
C, 60 min
pH = 8
CO
CO
OC
OH2H2O
OH2
+
99m
Tc
AEG complex
O
O
NO2
NO2
NO2
NO2
NO2
NO2

26. ‘Click’ Chemistry for radiolabeling with
[99mTc(CO)3(H2O)]+ core
3/18/2019 26
‘Click chemistry’  Copper catalyzed Huisgen type 1,3-dipolar cycloaddition
MILD REACTION CONDITIONS

27. 3/18/2019 27
Neutral complex

28. 3/18/2019 28

29. “4 + 1” Chemistry
3/18/2019 29
“4 + 1” core of 99mTc
(NS3 core of 99mTc)
NS3 ligand 99mTc-NS3 core
X – any labile ligand

30. 3/18/2019 30

31. Hynic chemistry
• Hynic – Hydrazino nicotinic acid
3/18/2019 31
Acts as a mono dentate ligand

32. • 99mTc forms hexa coordinate systems
• Co-ligands are required for radiolabeling with Hynic-ligand
• Ethylene diamine diacetic acid (EDDA) is an excellent co-ligand
3/18/2019 32
Hynic-99mTc-complex

33. HYNIC-TOC
Do not disturb!!
NHS-ester of Hydrazino nicotinic acid (HYNIC)
TOC
3/18/2019 33

34. Radiolabeling with gallium-68
3/18/2019 34
• Most stable oxidation state of gallium-68 is +3
• Unlike technetium-99m and rhenium-186/188 no reducing agent is required for
radiolabeling
Complexes are relatively unstable
compared to macro-cyclic chelators
Gallium-68
Half-life – 67.7 min
Positron

35. 3/18/2019 35
N’,N-bis(2-hydroxybenzyl)
ethylendiamin-N, N’-diacetic acid
1,4,7,10-tetraaza
cyclododecane, 1,4,7,10-
tetraacetic acid
N,N’,N”-(1,4,7-triaza
cyclononane-1,4,7-triyl)
triacetic acid
Radiolabeling with gallium-68

36. 3/18/2019 36
N’,N-bis(2-hydroxybenzyl)
ethylendiamin-N, N’-diacetic acid
Radiolabeling with gallium-68

37. 3/18/2019 37
N,N’,N”-(1,4,7-triaza cyclononane-
1,4,7-triyl) triacetic acid
Radiolabeling with gallium-68

38. 3/18/2019 38
1,4,7,10-tetraaza cyclododecane,
1,4,7,10-tetraacetic acid
Radiolabeling with gallium-68

39. Radiolabeling with lanthanides
3/18/2019 39
Important radiolanthanides for medical applications:
• Holmium-166, Samarium-153, Thulium-170 etc.
Lutetium-177
Half-life – 6.7 days
Gamma
Beta - 497 keV
- 176 keV
- 384 keV
Yttrium-90
Half-life – 64.1 h
Beta – 2.28 MeV

40. 3/18/2019 40
1,4,7,10-tetraaza cyclododecane,
1,4,7,10-tetraacetic acid
Radiolabeling with gallium-68

41. Opportunities…
• New ligands for:
– technetium-99m (Rhenium-188)
– gallium-68
– copper-64
– lanthanides (Lutetium-177, yttrium-90, Holmium-166 etc.)
3/18/2019 41

42. • New peptides for:
– Neuroendocrine cancers
– Prostate cancer
– Any other cancer
3/18/2019 42
Opportunities…

43. • Nanoparticle/Liposome based radiopharmaceuticals:
3/18/2019 43
Opportunities…
Targeting moiety
(Peptides/biomolecules)

44. THANK YOU....
3/18/2019 44