Metal complexes used in medicine

Question 1

Medical use of ionising radiation

Answer 1

Radiation therapy

Question 2

Alpha radiation

Answer 2

Two protons and two neutrons, identical to He nucleus

Question 3

Beta radiation

Answer 3

High-energy, high-speed electrons or positrons

Question 4

Gamma radiation

Answer 4

A form of high energy electromagnetic radiation

Question 5

Most common gamma-emitting radionuclide

Answer 5

99mTc

Question 6

Most common positron-emitting radionuclide

Answer 6

18F

Question 7

Design requirements for a radio-imaging probe

Answer 7

Stable containment of imaging agent
Lipophilic
Biological targeting using antibody/recognition motifs
Kinetically inert metal-chelate complex

Question 8

Neutral metal complex

Answer 8

Brain imaging

Question 9

Cationic metal complex

Answer 9

Heart imaging

Question 10

Anionic metal complex

Answer 10

Kidney imaging

Question 11

Neutral, lipophilic metal complex

Answer 11

Liver imaging

Question 12

Phosphato metal complex

Answer 12

Bone imaging

Question 13

Half life of 99mTc

Answer 13

6 hours

Question 14

Brain imaging agents

Answer 14

ECD (ethylenecysteine diethylester)
Ceretec
TRODAT - Tc(V) chelate conjugated to a cocaine derivative specific for dopamine receptors in the brain (used to diagnose Parkinson’s at early stage)

Question 15

Heart imaging agents

Answer 15

Tc(I) hexaisocyanide (“Cardiolite”)
Myoview

Taken up by myocardial muscle

Question 16

Bone imaging agents

Answer 16

Diphosphonates form a range of complexes with TcO4^-
All have free O groups that bind to the surface of the bone

MDP (methylenediphosphonate)

Question 17

Kidney imaging agents

Answer 17

Tc MAG-3

Tc-DMSA

Question 18

Second generation imaging agents

Answer 18

Stable neutral Tc chelate conjugated to a cyclic peptide binds to receptors expressed in certain forms of breast cancer

Question 19

Cu radioisotopes

Answer 19

62Cu = beta+
64Cu = beta+ and beta-
67Cu = beta- and gamma

Question 20

Use of copper-based imaging

Answer 20

Imaging hypoxia
Cu(II) reduced to Cu(I) in the cytosol
Radioactive Cu accumulates and is incorporated into the cell’s Cu metabolism

Question 21

Most successful metal drug

Answer 21

Cis-platin
[PtCl2(NH3)2]
Trans isomer inactive

Question 22

Side effects of cis-platin

Answer 22

Nephrotoxicity
Neurotoxicity
Nausea

Question 23

Pharmacology of cis-platin

Answer 23

70-90 % removed from blood serum within 15 mins of injection
More than half of dose excreted, other half distributed to all tissue with highest conc in kidney, uterus, skin and liver

Question 24

Mechanism of action of cis-platin

Answer 24

Cis-platin is neutral so can diffuse across the cell membrane
Low [Cl-] inside cell so cis-platin hydrolyses stepwise
[PtCl2(NH3)2] —> PtCl(H2O)(NH3)2]+ —> [Pt(H2O)2(NH3)2]2+
Loss of Cl permits binding of Pt to guanine N7 in DNA
(can also bind to other bases but weaker)

Question 25

Half life of cis-platin in H2O

Answer 25

10 hours | Accounts for lag in observed activity after addition to cells

Question 26

Half life of cis-platin in H2O

Answer 26

10 hours | Accounts for lag in observed activity after addition to cells

Question 27

Mode of binding of cis-platin to DNA

Answer 27

Pt initially binds in a monodentate fashion (not important for cis-platin toxicity) Then binds to either Two guanine residues on the same strand (intrastrand binding, accounts for majority of [Pt]-DNA adducts) Two guanine residues on parallel strands (inter strand binding, accounts for 1 % of [Pt]-DNA adducts) Binding of Pt(II) causes the bending and unwinding of the DNA helix

Question 28

New Pt-based anti-cancer complexes

Answer 28

Carboplatin - 2nd gen, less nephrotoxic Nedaplatin JM 216 - trans complex also active! Effective against cis-platin-resistant tumours BBR 3464 - central Pt binds to DNA via H-bonding, positive charge enhances intrastrand DNA interaction and causes significant unwinding

Question 29

Structure-effect relationship in platinum complexes of relevance for cancer therapy

Answer 29

Square planar Pt(II) or octahedral Pt(IV) (less effective) Cis configuration generally required Two cis "non-leaving" ligands required, preferably N-based with at least one NH for H-bonding Two leaving ligands with intermediate stability and exchangeable on therapeutic timescale Complex must initially be neutral to pass through cell membrane

Question 30

Other important metal complexes for the treatment of cancer

Answer 30

Cp2TiCl2 Budotitane Ru indazole complex

Question 31

PET

Answer 31

Positron Emission Tomography Uses radionuclides that emit positrons e.g. 18F The emitted positrons combine with electrons to produce gamma rays that travel in exactly opposite directions ("positron annihilation")

Question 32

SPECT

Answer 32

Single Photon Emission Computed Tomography | Uses radionuclides that emit gamma radiation e.g. 99mTc

Question 33

How are the radionuclides for PET scanning produced?

Answer 33

In a cyclotron