Chelation is a core principle in Coordination Chemistry

A brief description of chelation as a core principle of coordination chemistry

I have been able to appreciate the one positive aspect of various posers disputing: gadolinium toxicity, using the term GDD, chelation; is that it has forced me to understand the science better. So in many respects I do have all these contrarians to thank for this.

Let us start with the big picture and history. Coordination chemistry has been formally established since the late 19th century. Alfred Werner is considered the father of coordination chemistry, developing his work in the 1890s, and received the Nobel Prize for this in 1913.

Coordination chemistry entails how ligands (read chelators) bind to a central metal ion. Chelation is a specific form in which ligands form multiple bonds, creating stable ring (ring-like) structures. Chelation is a major central concept in the field. Metal ions bond to a chelator on the basis of coordination geometry (bonding site orientation). The better alignment of these sites with the metal the higher the log K (binding strength). Thus higher log K values comparing chelators reflect what coordinate chemists would term more favorable coordination site geometry. I prefer to use, as it is more intuitive, that the orientation of the binding sites are a better fit for the coordination sites (attachment points) of the metal ion. These coordination sites on the metal ion are the specific orbital regions where the metal accepts electron pairs from the chelator. In the simplest terms the better the chelator, the higher the log K, reflecting the better binding site orientations. It is also important to understand that in a complex physiological system like the human body, chelator competition is constantly ongoing, and the better orientation fits, the more of those complexes develop, compared to weaker bonding. Log K is the intrinsic' binding strength', which is a term I find more easy to grasp.

Kinetic stability is another central aspect of chelate bonding, and this refers to the rate of dissociation of the metal ion from the ligand/chelator, generally expressed as half life. Half life is the time for 1/2 of the Gd to be dissociated from the ligand/chelator. This 'temporal stability' depends on the intrinsic bonding strength but also with 'steric factors' meaning how well the chelator's structure fits around the metal, and 'electrostatic interactions' which are based on charge distribution. In short temproal stability, how long the metal-ligand stays intact is based on intrinsic bonding strength, geometric fit, and charge interactions.

Focusing the circle now to deal with GBCAs and use in humans. Gd agents are based on coordinate chemistry and are in the large category of chelation. Both macrocyclic and linear agents form ring-like structures around the Gd atom, where macrocylic agents are complete rings and linear are incomplete rings. So the term linear is really a misnomer, they really are agents that form incomplete ring. The steric factor of a complete ring renders essentially all macrocyclic agents with a longer duration of remaining intact (higher kinetic stability) compared to linear (non-complete ring) agents. This is however different than their intrinsic bonding strength. Two of the macrocyclic agents actually have lower bonding strength (meaning slightly inferior orientation of bonding sites to the Gd metal ion) than some linear agents, and notably DTPA. This is the case with Gadavist and Gadopiclenol (the newest MR GBCA). Lower intrinsic bonding strength may be seen as a disadvantage, superficially, but there is an advantage to this. It means that DTPA is better able to remove these agents because it has higher intrinsic stability and can remove Gd, from these agents if they are retained and have resulted in GDD. This will be addressed more fully in a future blog. The ability of linear chelators to wrap around a metal makes them much better chelators than macrocyclic chelators. This is not only from the dynamic fitting, but also because macrocyclic agents generally require much higher temperatures to create (200 degrees C) whereas linear chelators, due to their dynamic wrapping, can be created under physiological conditions. I believe I have blogged that before.

Just to further complete knowledge on coordination chemistry in humans. Native metalloproteins (of which there are more than 50 types) form coordination bonds between the protein's donor atoms and the metal ion. Most metalloproteins have Zn as the core metal ion. Transferrin is also a metalloprotein, and its core is iron. Gd can substitute in for iron in transferrin.

So all of the above as a group can be described in the most scientific terms as coordination complexes. These include the metalloproteins in our body, which number > 50, and are essential for us to survive.

Ironically, I do have to thank all the naysayers for forcing me to understand more of the inner dolls in a stacking Matroyschka doll of medical science. So if you read and re-read this blog you will know more about the crucial aspect of coordination chemistry and chelation, than any radiologist (except me of course) and any kidney doctor, or neurologist, etc. To say that mechanistically chelation doesn't make sense exposes that atleast in this critical aspect of medicine you are a fool. but more specifically a poser.

I have created this saying, in dealing with the other gaggle of posers who think chelation is not safe:

Anything that works well, if performed incorrectly, is fundamentally dangerous.

I think I have said this in earlier blogs, where I have explained things clearly, that I hope this is the last time I have to say it. But somehow stupidty has a way of always rearing its ugly head. Each Nightmare on Elm Street movie ends with Freddy Krueger being brutally murdered, and yet somehow a year or so later he has come back to life again in a sequel. So yes obviously it would be best if this disparate collection of posers, fools, block-heads, and pathologic enviers would just shut up, because they cause, and maybe intentionally so, considerably more harm than anything good. But I have to brace myself in a Machievellian way:

A fool and his foolish words are never parted

Ending on a positive note. A number of physicians and others have said things like 5% of medicine is actually known. This actually is an incorrect way of thinking about knowledge. Knowledge really is the process of opening a stacking doll. A wise practitioner realizes that maybe he has opened 6 stacking dolls (when the next most accomplished person may be has opened 3) but he/she realizes there are still atleast 6 more stacking dolls inside. Another metaphor is that knowledge proceeds in a layered fashion, and the word palimpsest best describes this.

DTPA chelation is presently the best method to treat GDD, and a number of other metal DD, like lead DD, Cadmium DD, and inorganic Mercury DD. Disputing DTPA chelation is a reflection of ignorance of coordination chemistry.

Richard Semelka, MD