Metal complexes used in medicine Flashcards
Medical use of ionising radiation
Radiation therapy
Alpha radiation
Two protons and two neutrons, identical to He nucleus
Beta radiation
High-energy, high-speed electrons or positrons
Gamma radiation
A form of high energy electromagnetic radiation
Most common gamma-emitting radionuclide
99mTc
Most common positron-emitting radionuclide
18F
Design requirements for a radio-imaging probe
Stable containment of imaging agent
Lipophilic
Biological targeting using antibody/recognition motifs
Kinetically inert metal-chelate complex
Neutral metal complex
Brain imaging
Cationic metal complex
Heart imaging
Anionic metal complex
Kidney imaging
Neutral, lipophilic metal complex
Liver imaging
Phosphato metal complex
Bone imaging
Half life of 99mTc
6 hours
Brain imaging agents
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)
Heart imaging agents
Tc(I) hexaisocyanide (“Cardiolite”)
Myoview
Taken up by myocardial muscle
Bone imaging agents
Diphosphonates form a range of complexes with TcO4^-
All have free O groups that bind to the surface of the bone
MDP (methylenediphosphonate)
Kidney imaging agents
Tc MAG-3
Tc-DMSA
Second generation imaging agents
Stable neutral Tc chelate conjugated to a cyclic peptide binds to receptors expressed in certain forms of breast cancer
Cu radioisotopes
62Cu = beta+ 64Cu = beta+ and beta- 67Cu = beta- and gamma
Use of copper-based imaging
Imaging hypoxia
Cu(II) reduced to Cu(I) in the cytosol
Radioactive Cu accumulates and is incorporated into the cell’s Cu metabolism
Most successful metal drug
Cis-platin
[PtCl2(NH3)2]
Trans isomer inactive
Side effects of cis-platin
Nephrotoxicity
Neurotoxicity
Nausea
Pharmacology of cis-platin
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
Mechanism of action of cis-platin
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)
Half life of cis-platin in H2O
10 hours
Accounts for lag in observed activity after addition to cells
Half life of cis-platin in H2O
10 hours
Accounts for lag in observed activity after addition to cells
Mode of binding of cis-platin to DNA
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
New Pt-based anti-cancer complexes
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
Structure-effect relationship in platinum complexes of relevance for cancer therapy
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
Other important metal complexes for the treatment of cancer
Cp2TiCl2
Budotitane
Ru indazole complex
PET
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”)
SPECT
Single Photon Emission Computed Tomography
Uses radionuclides that emit gamma radiation e.g. 99mTc
How are the radionuclides for PET scanning produced?
In a cyclotron
