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I didn't quite get a chance to
tell you a few things about

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photosystem II last time,
so I am going to go ahead and

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finish up with that now before
going onto the Cardiolite story.

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Photosystem II shares quite a
lot in common with photosystem

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I, but there are a few major
differences.

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Photosystem II is the first
link in the chain of

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photosynthesis.
It is really where all

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photosynthesis starts out on
earth.

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And, as such,
it is an extraordinarily

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important enzyme,
this photosystem II.

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But it is such a large and
complicated enzyme.

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And it is also a membrane
enzyme.

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As I mentioned last time,
these are difficult to isolate

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and purify and crystallize so
that you can study their

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structures.
And it was only in the last

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couple of years that photosystem
II was actually

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crystallographically
characterized,

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so there is really a lot of
very recent science that is

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relevant to today's presentation
on photosystem II.

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As you go through and read
about it, you are going to learn

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about the molecules that harvest
the light, and you are going to

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learn about where the electron
goes and where the hole goes

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when light is absorbed by this
amazing system.

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Here is a close up of part of
the system called the reaction

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center, for obvious reasons.
This where the reactions take

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place that are so integral to
photosynthesis.

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Namely we have,
up here at the top,

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a manganese-containing cluster,
the structure of which is still

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a little bit ill-defined.
As you can imagine,

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with a macromolecule of this
size, it is difficult to say

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exactly where just each and
every atom is in the structure.

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There are still some details of
the structure,

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of the manganese cluster,
here, that are not known.

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But, nonetheless,
this is where two water

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molecules must be brought in and
coordinated and ultimately where

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water, which is not a good
reducing agent,

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serves as a source of electrons
in this system.

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And what happens is this
special pair of chlorophyll

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molecules at the heart of the
reaction center absorbs a photon

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and goes into an excited state.
And the electron is able to

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travel down through a series of
pigment molecules,

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and it gets down onto this
plastoquinone A.

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And it is able to jump over
onto the plastoquinone B.

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And plastoquinone B then can
dissociate from the reaction

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center and carry that electron
onto the next link in the chain

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in photosynthesis.
And, at the same time,

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the hole is stuck back over
here and ends up accepting an

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electron by oxidation of a
reduced tyrosine moiety here.

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This tyrosine has a phenoxy
residue.

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It is connected to the amino
acid polypeptide backbone of

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this protein and it is
positioned right here between

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the manganese cluster and the
special pair,

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so that once the electron is
shuttled away down this redox

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cascade pathway,
it is juxtaposed with this

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reduced tyrosine,
which is getting its electrons

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from the water that is
coordinated to the manganese

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complex.
And somehow those two water

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molecules, after giving up their
four electrons,

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become O two.
And O two gas bubbles out,

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and that is the source of the
oxygen that we breathe on this

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planet.
So this is, needless to say,

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a very important enzyme to
understand.

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And I won't have time to go
through an exploration of the

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structure today,
but I will lead you into it by

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showing you this picture.
And in this picture,

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the sort of gray background
that is mapped out here on the

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outside represents this
polypeptide chain,

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all the amino acids that are
linked together to form the

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protein container of photosystem
II.

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And you can see that it looks
like a dimeric structure where

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you have one reaction center
over here, here is a special

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pair located over there.
And then all embedded

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throughout this protein you find
many, many cofactors which are

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like porphyrins,
but contain magnesium.

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And there are these chlorophyll
units.

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And then also,
shown in sort of an orange

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color here, you see these long
straight molecules.

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These are polyenes.
These are carotenoid molecules,

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organic molecules that have
strings of double bonds adjacent

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to one other so that they can
conduct electricity and conduct

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energy.
And this is a really key

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feature of this --
-- because the point that is

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being made here is that the
photosynthesis does not wait

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until a photon actually comes in
and impinges right there on the

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special pair.
A photon can come in anywhere

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on this big molecule or on these
light harvesting proteins shown

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at top and at bottom that come
up and dock next to photosystem

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II.
And these light harvesting

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proteins are also just chalk
full of light absorbing

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chromophores,
chlorophylls,

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and carotenoid molecules.
And, if a photon comes in and

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excites one of these molecules
over here, the proton has a

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mechanism for transmitting the
energy over to the special pair,

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so that water can be oxidized
to O two.

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It is really quite a tremendous
assembly of different kinds of

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molecules to perform function.
And if you go on and take 5.03,

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for example,
and then 5.04,

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you will learn about the rules
that govern electron transfer

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between molecules and also in
proteins.

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Let's see.
Finally, on this subject,

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I will show you,
here, a view of this reaction

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center.
And this just a close-up to

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show you that these water
molecules indeed must get in

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here.
There is also a calcium ion

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present at this active site,
where the water molecules are

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being oxidized and converted
into dioxygen.

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And here is that tyrosine
residue shown in more detail.

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That is very important for the
hopping of the electron from

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water to the tyrosine.
And then over here,

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after the hole has been
generated through excitation of

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the special pair of chlorophyll
molecules.

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And so that brings me to the
end of my discussion of

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six-metaloenzyme systems that
had quite a bit in common in

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terms of the ligands that are
used to bind metals.

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We talked about heme last time
and its employment of the

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porphyrin ligand in this regard.
But then, you should also

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remember that sometimes you see
clusters packed into protein

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molecules as cofactors.
We saw last time some Fe four-S

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four clusters,
and here, a manganese cluster.

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And so inorganic and organic
molecules are all working

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together in a beautiful synergy
to enable photosynthesis.

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And, having said that,
I would like to now go onto my

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final topic, which has to do
with the role that metals can

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play in medicine.
Last time was metals in

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biology.
Now, we will talk about metals

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in medicine.
And there are different ways

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that metals can be used in
medicine.

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For example,
there are molecules like

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cisplatin that are used in
therapeutic methods for treating

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cancer.
Alternatively,

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metals can be used in a
diagnostic manner.

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And that is what I will be
talking about here today.

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And so what I did for today was
I went directly to a couple of

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the Ph.D.
theses that are in the MIT

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digital archive by two students
who worked in the Chemistry

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Department here and earned their
Ph.D.

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theses doing the chemistry of
technetium.

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Now, I like technetium for a
lot of reasons.

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One, it is a neighbor element
to molybdenum in the periodic

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table.
Number two, it is named after

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MIT, so that is wonderful.
Number three,

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technetium is unique as an
example, right in the center of

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the periodic table,
as a manmade element.

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And it has been known for quite
some time, and I am going to

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tell you a little bit how
technetium chemistry has evolved

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in the MIT Chemistry Department.
And so this first thesis is a

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1983 thesis of a fellow by the
name of Mike Abrams,

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a very smart graduate student
who was given a very difficult

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research problem indeed for his
Ph.D.

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thesis.
And that had to do with

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preparing compounds directly
from the pertechnetate ion.

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And pertechnetate is the ion
TcO four minus.

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And, if you look through this,
you will see why Mike Abrams

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needed to prepare compounds
directly from the pertechnetate

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ion.
And it has to do with the idea

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that there is an isotope of
technetium.

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An isotope known as
technetium-99M,

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M for metastable,
that has a six hour half-life.

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And, in that six hour time
window that is the half-life of

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technetium-99M,
it is dropping from a nuclear

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excited state into a nuclear
ground state.

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And I will talk more about that
in a moment.

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But as the nuclear excited
state relaxes to the ground

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state, this nucleus emits a
single gamma photon at about

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kiloelectron volts.
And so that single gamma

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photon, high energy photon,
that comes out when this

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nucleus decays from 99M to
regular technetium-99,

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which has a much longer
half-life on the order of 10^5

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years, is what is useful in a
branch of medicine known as

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nuclear medicine.
So radiologists will be

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interested in this.
And, as you will see,

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cardiologists will be
interested in this as well.

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And so, because of this,
gamma camera images can be

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obtained at high-resolution to
image organs that have taken up

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this radioisotope.
Let's point out also,

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here, that the chemical form of
technetium obtained from the

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generator that creates it is the
pertechnetate ion,

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so all radiopharmaceuticals
have to be prepared from TcO

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four minus because
that is what you get.

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Molybdenum-99 is a product of
nuclear fission.

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And so, when people are using
nuclear reactors to make energy,

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they are accumulating a lot of
molybdenum-99.

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And molybdenum-99 is an
unstable isotope of molybdenum,

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and so it is right to the left
of technetium on the periodic

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table.
And molybdenum-99 itself

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undergoes a beta decay,
in which a neutron turns into a

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proton and electron.
And that beta decay converts

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molybdenum-99 into this
metastable isotope of

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technetium.
So what happens is that every

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morning at the hospital,
the molybdenum-99 has been

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coated as MoO four onto
an alumina column and is

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undergoing its own beta decay.
And when that is done,

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you now have pertechnetate on
the column.

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And you can elute that in very
dilute solution,

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in isotonic saline solution.
You then have a very small

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amount of time to do chemistry
with it before you put it in the

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body.
Therefore, Mike Abrams,

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and I will tell you about the
professors involved in this in a

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little bit, was given the
problem of finding a way to take

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an extremely dilute solution on
the order of 10^-9 molar

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solution in saline and do a
quantitative reaction from

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pertechnetate to make something
that would go and localize in an

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organ that you want to image to
find out about the patient's

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health.
That is a tall order,

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but that didn't stop them from
looking into this.

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In fact, I included this page
in part, because Mike Abrams has

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00:13:02 --> 00:13:05
some nice statements,
here.

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He says the reason we carried
out this research was to gain a

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better understanding of what
kinds of coordination complexes

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can be prepared directly from
TcO four minus with

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the hope that such information
might lead to the development of

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00:13:19 --> 00:13:22
new radiopharmaceutical agents
and/or to a better understanding

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00:13:22 --> 00:13:24
of the agents already in
clinical use.

218
00:13:24.918 --> 1983.
This thesis was written in

219
1983. --> 00:13:26


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00:13:26 --> 00:13:30
Well, let me not get ahead of
myself here.

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And let me just show you here
one of the first technetium

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00:13:34 --> 00:13:38
complexes that Mike Abrams was
able to prepare.

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And this is a technetium
hexacis thyourea species.

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You will see that he has this
pertechnetate and was able to

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convert it into molecules that
are octahedral at technetium.

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00:13:52 --> 00:13:55
And, in fact,
most of the applications of

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technetium in nuclear medicine
do involve octahedral

228
00:13:59 --> 00:14:03
six-coordinate technetium,
--

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00:14:03 --> 00:14:07
-- harkening back to what we
can understand based on the

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efforts and achievements of
Alfred Werner.

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00:14:10 --> 00:14:13
Here is the octahedron,
pretty soon,

232
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going to go into a patient's
body.

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Here he has chosen to use
sulfur donor ligands,

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these thiourea ligands in
making this.

235
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And he also made molecules in
which phosphines and phosphites

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were able to bind to technetium.
And later, as you will see,

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he also did work with
isocyanides.

238
00:14:34 --> 00:15:00


239
00:15:00 --> 00:15:03
This is 90 degrees rotated.
Basically, the reason I am

240
00:15:03 --> 00:15:07
showing you this is that this is
a nuclear magnetic resonance

241
00:15:07 --> 00:15:09
spectrum of a technetium-99
compound.

242
00:15:09 --> 00:15:12
Let me just explain that
initially, when doing these

243
00:15:12 --> 00:15:16
studies, Mike Abrams was working
mostly with technetium-99 that

244
00:15:16 --> 00:15:20
has the real long half-life so
you can actually make molecules

245
00:15:20 --> 00:15:25
on a scale sufficient for
isolation and purification.

246
00:15:25 --> 00:15:30
But then those methods would be
translated to working with the

247
00:15:30 --> 00:15:34
99M isotope.
And the difference between 99

248
00:15:34 --> 00:15:38
and 99M, has to do with the spin
of the nucleus.

249
00:15:38 --> 00:15:41
We have talked about electron
spin.

250
00:15:41 --> 00:15:46
Well, different nuclei have
themselves the property of spin.

251
00:15:46 --> 00:15:51
And technetium-99 has a spin
one-half nuclear spin.

252
00:15:51 --> 00:15:56
And then when it decays from
99M to 99, the 99 isotope has a

253
00:15:56 --> 00:16:00
spin nine-halves,
actually.

254
00:16:00 --> 00:16:04
And that is the lower energy
state that gives rise to this

255
00:16:04 --> 00:16:08
gamma photon emission.
And so, in the nuclear magnetic

256
00:16:08 --> 00:16:11
resonance spectrum,
observing the phosphorus 31

257
00:16:11 --> 00:16:15
nuclei that are connected to
this hexakisphosphate of

258
00:16:15 --> 00:16:18
technetium 1,
you see that there end up being

259
00:16:18 --> 00:16:22
ten lines.
And that is because of the spin

260
00:16:22 --> 00:16:27
nine-halves ground state of the
technetium-99 nucleus.

261
00:16:27 --> 00:16:30
You will see that back in the
`80s, we were looking at

262
00:16:30 --> 00:16:34
technetium-coupled phosphorus
NMR spectra, as well as,

263
00:16:34 --> 00:16:37
you saw X-ray crystallography a
moment ago.

264
00:16:37 --> 00:16:41
This was real nice work.
And let's see what I have here.

265
00:16:41 --> 00:16:45
After Mike had successfully
synthesized some of these

266
00:16:45 --> 00:16:48
complexes they started
wondering, well,

267
00:16:48 --> 00:16:51
can we image organs with these.
The idea was that

268
00:16:51 --> 00:16:55
radiopharmaceuticals that had
been in use prior to this time

269
00:16:55 --> 00:17:00
did not really have ligands on
the metal.

270
00:17:00 --> 00:17:03
It was sort of the case that
they would take the metal in

271
00:17:03 --> 00:17:06
whatever form they got it off a
generator and just inject it

272
00:17:06 --> 00:17:09
directly into the patient.
And, in that case,

273
00:17:09 --> 00:17:12
you don't have an ability to
tune the properties of the metal

274
00:17:12 --> 00:17:16
to have it localize specifically
at organs that you might want to

275
00:17:16 --> 00:17:18
image.
And so they thought we are

276
00:17:18 --> 00:17:20
coordination chemists.
Let's put ligands on there,

277
00:17:20 --> 00:17:22
and you can use different
ligands.

278
00:17:22 --> 00:17:26
And then, the molecule will go
to different parts of the body

279
00:17:26 --> 00:17:29
specifically.
And, when we find the right

280
00:17:29 --> 00:17:32
ligand, we will be able to do
something useful,

281
00:17:32 --> 00:17:34
like image the heart.
And so here,

282
00:17:34 --> 00:17:38
they had an anesthetized dog
that they had injected with a

283
00:17:38 --> 00:17:41
solution of one of these
technetium complexes.

284
00:17:41 --> 00:17:44
This was a hexakis isobutyl
isocyanide technetium-99M.

285
00:17:44 --> 00:17:48
And they were able to show that
this stuff forms quantitatively,

286
00:17:48 --> 00:17:52
even at the tracer levels that
they are using to 10^-9 molar.

287
00:17:52 --> 00:17:56
Very dilute solutions.
And so you don't actually get

288
00:17:56 --> 00:18:00
much radioactivity put into you,
but because of the high energy

289
00:18:00 --> 00:18:04
nature of the gamma photons that
come out, you can easily image

290
00:18:04 --> 00:18:07
them with a gamma camera and you
can reconstruct the position

291
00:18:07 --> 00:18:10
from which that radiation is
originating.

292
00:18:10 --> 00:18:12
That is what allows you to
image an organ.

293
00:18:12 --> 00:18:15
And so here is a little
schematic of the ribcage of a

294
00:18:15 --> 00:18:17
dog.
And you can see that he is

295
00:18:17 --> 00:18:21
telling us where the liver is.
And then you are supposed to be

296
00:18:21 --> 00:18:25
able to see kind of a doughnut,
which is the myocardium of the

297
00:18:25 --> 00:18:28
heart here.
And you see it lighting up real

298
00:18:28 --> 00:18:30
nice, right here.
So right away,

299
00:18:30 --> 00:18:33
with one of the first complexes
that they made,

300
00:18:33 --> 00:18:37
they found that this stuff goes
shortly after injection and

301
00:18:37 --> 00:18:40
localizes in the heart and gives
you a pretty nice image of the

302
00:18:40 --> 00:18:42
heart.
And there are different

303
00:18:42 --> 00:18:46
viewpoints that you can take
when you image the heart using

304
00:18:46 --> 00:18:49
methods like this,
but this was already pretty

305
00:18:49 --> 00:18:52
exciting that one of the first
systems they made,

306
00:18:52 --> 00:18:55
these t-butyl groups on it,
were very nice imaging agents

307
00:18:55 --> 00:18:59
for a dog.
And then the basis for the

308
00:18:59 --> 00:19:03
nuclear cardiology application
of this chemistry is that if a

309
00:19:03 --> 00:19:07
person has had a heart attack or
is at-risk to suffer a heart

310
00:19:07 --> 00:19:10
attack, has some heart disease,
then what happens is you look

311
00:19:10 --> 00:19:14
at the heart and it doesn't
become very well-perfused with

312
00:19:14 --> 00:19:17
blood all the way around,
as it should in a normal

313
00:19:17 --> 00:19:20
healthy heart.
And so, if there is infarcted

314
00:19:20 --> 00:19:23
tissue, you see an image like
this, where part of the doughnut

315
00:19:23 --> 00:19:28
is not lighting up.
And that means that part of the

316
00:19:28 --> 00:19:31
heart is not getting suffused
with blood.

317
00:19:31 --> 00:19:35
And so this kind of diagnostic
test is called myocardial

318
00:19:35 --> 00:19:38
perfusion imaging,
because you are looking at how

319
00:19:38 --> 00:19:42
the heart is taking up blood in
all of its different parts

320
00:19:42 --> 00:19:46
because you can look at
different angles of view.

321
00:19:46 --> 00:19:50
And one also tends to do this
when the subject is at rest

322
00:19:50 --> 00:19:53
versus when the subject has been
stressed.

323
00:19:53 --> 00:19:57
So you will hear the term
stress test associated with this

324
00:19:57 --> 00:20:02
type of image.
And so this is really the first

325
00:20:02 --> 00:20:05
complex that Mike Abrams made
that they were actually testing

326
00:20:05 --> 00:20:08
in animals.
Here was an infarcted dog

327
00:20:08 --> 00:20:10
heart.
You see that there is blood not

328
00:20:10 --> 00:20:13
getting to this part of the
heart, up here.

329
00:20:13 --> 00:20:16
And this image was to be
compared with an image made

330
00:20:16 --> 00:20:20
using a different imaging agent
which was the state of the art

331
00:20:20 --> 00:20:23
at the time, here,
with just the first one.

332
00:20:23 --> 00:20:27
And there were so many choices
you could make of what ligand to

333
00:20:27 --> 00:20:32
put on this metal.
And the first one already works

334
00:20:32 --> 00:20:36
better than thallium-201 that is
inserted just as an aqueous

335
00:20:36 --> 00:20:38
solution.
So thallium-201 is also a

336
00:20:38 --> 00:20:41
popular isotope for applications
in nuclear medicine,

337
00:20:41 --> 00:20:44
but with technetium,
now, you have the ability to

338
00:20:44 --> 00:20:48
make coordination compounds
where the ligands are very

339
00:20:48 --> 00:20:50
tightly bonded to the metal
center.

340
00:20:50 --> 00:20:54
And then you can attach other
residues to this system by

341
00:20:54 --> 00:20:56
virtue of how you build the
ligands.

342
00:20:56 --> 00:21:01
That was really pretty amazing.
And then a few years later,

343
00:21:01 --> 00:21:04
also in the research group of
Alan Davison,

344
00:21:04 --> 00:21:09
Professor of Chemistry at MIT,
comes along one James Frederick

345
00:21:09 --> 00:21:11
Carnegie.
And what he decided to do for

346
00:21:11 --> 00:21:16
his thesis work was to go ahead
and actually make molecules like

347
00:21:16 --> 00:21:20
the ones that Mike Abrams made,
but to look at many different

348
00:21:20 --> 00:21:24
varieties with different
peripheral substituents because

349
00:21:24 --> 00:21:28
there are certain organic
functional groups that will be

350
00:21:28 --> 00:21:33
metabolized and chopped up by
enzymes in the body.

351
00:21:33 --> 00:21:36
These include ester groups,
for example.

352
00:21:36 --> 00:21:40
You can also attach to these
isocyanide ligands things that

353
00:21:40 --> 00:21:44
look like little proteins.
And you can see,

354
00:21:44 --> 00:21:47
then, how those react to being
injected.

355
00:21:47 --> 00:21:52
And so his goal here was really
to make something practical that

356
00:21:52 --> 00:21:56
would be useful as a
radiopharmaceutical for imaging

357
00:21:56 --> 00:22:00
organs.
And his discussion begins by

358
00:22:00 --> 00:22:04
just talking about the different
groups that he was going to

359
00:22:04 --> 00:22:08
append to the surface of his
coordination complex.

360
00:22:08 --> 00:22:12
And then, here is a little
synthesis slide from his thesis.

361
00:22:12 --> 00:22:15
Mike Abram's thesis,
the first one I showed you,

362
00:22:15 --> 00:22:19
was actually typed up by hand
on a typewriter.

363
00:22:19 --> 00:22:22
But Jim Carnegie's thesis was
prepared, he tells me,

364
00:22:22 --> 00:22:27
I was talking to him last night
about this, using a very

365
00:22:27 --> 00:22:31
primitive word processor.
One of the first-generation

366
00:22:31 --> 00:22:34
word processors.
Anyway, that is a little bit

367
00:22:34 --> 00:22:38
beside the point.
You just don't see as many nice

368
00:22:38 --> 00:22:42
graphics in these theses as you
do nowadays, but you do see a

369
00:22:42 --> 00:22:46
lot of beautiful chemistry.
Here is an isocyanide ligand.

370
00:22:46 --> 00:22:48
Look.
We have talked a lot about

371
00:22:48 --> 00:22:52
carbon monoxide in this class as
a ligand in its behavior to

372
00:22:52 --> 00:22:55
transition metals.
And so if you just change the

373
00:22:55 --> 00:23:00
oxygen of carbon monoxide into a
nitrogen, then you can have a

374
00:23:00 --> 00:23:04
substituent stuck to it.
Here is an example of an

375
00:23:04 --> 00:23:08
isocyanide ligand where the
metal is going to attach to the

376
00:23:08 --> 00:23:11
carbon.
And then, Carnegie decided to

377
00:23:11 --> 00:23:14
put other groups out here.
Here, he has a carboethoxy

378
00:23:14 --> 00:23:17
residue.
And the idea was that enzymes

379
00:23:17 --> 00:23:21
called esterases in the body can
clip off and metabolize the

380
00:23:21 --> 00:23:24
carboethoxy residue.
And what that will do is it

381
00:23:24 --> 00:23:28
will affect the way that the
technetium is bio-distributed in

382
00:23:28 --> 00:23:32
the body.
It will affect the kinetics of

383
00:23:32 --> 00:23:37
how long the technetium takes to
accumulate in an organ and how

384
00:23:37 --> 00:23:40
long it takes to then run out of
that organ.

385
00:23:40 --> 00:23:45
And also, he looked at examples
that have organic amide

386
00:23:45 --> 00:23:48
functional groups,
all connected to the

387
00:23:48 --> 00:23:51
isocyanide.
His thesis work was all about

388
00:23:51 --> 00:23:55
looking at different
isocyanides, six of them on

389
00:23:55 --> 00:23:59
technetium in the +1 oxidation
state.

390
00:23:59 --> 00:24:02
It is d^6 low-spin octahedral
diamagnetic systems.

391
00:24:02 --> 00:24:04
It talks here about the
radioactivity.

392
00:24:04 --> 00:24:08
It talks a little bit about the
technetium generator issue.

393
00:24:08 --> 00:24:11
It mentions that he is doing a
lot of this work in

394
00:24:11 --> 00:24:14
collaboration over at Harvard
Medical School.

395
00:24:14 --> 00:24:18
They had a lab over there where
they were cleared to use 99M.

396
00:24:18 --> 00:24:20
The 99 work was done here,
at MIT.

397
00:24:20 --> 00:24:24
And this was because of the
collaboration that I will tell

398
00:24:24 --> 00:24:27
you about shortly.
Here is one that I won't bother

399
00:24:27 --> 00:24:32
to turn over.
But this actually a pretty

400
00:24:32 --> 00:24:36
important slide.
You will get this pdf file from

401
00:24:36 --> 00:24:41
our website, but you will see
that he is taking pertechnetate

402
00:24:41 --> 00:24:44
and saline.
The key feature,

403
00:24:44 --> 00:24:49
here, is that this synthesis is
quantitative at these very low

404
00:24:49 --> 00:24:54
concentrations that are what
used for nuclear medicine.

405
00:24:54 --> 00:25:00
Now, I showed you that Mike
Abrams imaged part of a dog.

406
00:25:00 --> 00:25:03
And as they progressed toward
doing human studies,

407
00:25:03 --> 00:25:06
they also imaged the rabbit.
And in these early tests,

408
00:25:06 --> 00:25:09
you know, you have these
chemistry Ph.D.

409
00:25:09 --> 00:25:13
students who don't really know
which organ is which in a bunny.

410
00:25:13 --> 00:25:16
They had to get a diagram like
this, out so they would have a

411
00:25:16 --> 00:25:20
map, so that when they started
shooting these molecules into

412
00:25:20 --> 00:25:24
the bunny they would know which
organ they were seeing light up

413
00:25:24 --> 00:25:27
by the gamma camera.
And this does not hurt the

414
00:25:27 --> 00:25:31
bunny.
The bunny is anesthetized and

415
00:25:31 --> 00:25:33
does not know,
so this is a perfectly nice

416
00:25:33 --> 00:25:35
thing to do.
And this one,

417
00:25:35 --> 00:25:39
I think the bunny is oriented
this way, here is the liver.

418
00:25:39 --> 00:25:43
And resting atop the liver on
the diaphragm is the heart of

419
00:25:43 --> 00:25:46
the bunny right here.
He has a lot of different

420
00:25:46 --> 00:25:49
images.
These, in the digital thesis

421
00:25:49 --> 00:25:53
archive, are a little bit fuzzy.
If you want to see better

422
00:25:53 --> 00:25:58
images, you might want to refer
directly to the thesis.

423
00:25:58 --> 00:26:01
But you will see that what he
is doing here is he is looking

424
00:26:01 --> 00:26:05
as a function of time after
injection, just the intensity of

425
00:26:05 --> 00:26:08
the gamma counts from the liver,
from the kidney.

426
00:26:08 --> 00:26:11
Notice the heart starts out
real high, and then it clears as

427
00:26:11 --> 00:26:14
the blood moves on into the
kidney and the liver.

428
00:26:14 --> 00:26:18
And so you can actually take
these images as a function of

429
00:26:18 --> 00:26:21
time and see where the
technetium is going in this

430
00:26:21 --> 00:26:23
living bunny.
And I thought I would mention

431
00:26:23 --> 00:26:26
that.
But then, I thought I would

432
00:26:26 --> 00:26:30
also show you this picture.
I have seen this in the real

433
00:26:30 --> 00:26:32
hard copy thesis,
and it looks much better in

434
00:26:32 --> 00:26:35
terms of organs lighting up and
so forth.

435
00:26:35 --> 00:26:38
It is very fuzzy in this image
from Carnegie's Ph.D.

436
00:26:38 --> 00:26:39
thesis.
This, in fact,

437
00:26:39 --> 00:26:43
is Professor Alan Davison,
who was himself the first test

438
00:26:43 --> 00:26:46
subject for his technetium
radiopharmaceutical.

439
00:26:46 --> 00:26:49
He just couldn't wait to have
this stuff shot into him,

440
00:26:49 --> 00:26:53
so he could see what his organs
looked like when imaged with a

441
00:26:53 --> 00:26:55
gamma camera.
That is Professor Davison,

442
00:26:55 --> 00:27:00
first human test subject on his
own chemistry.

443
00:27:00 --> 00:27:04
That was pretty remarkable.
Let me tell you just a little

444
00:27:04 --> 00:27:09
bit more about Alan Davison.
You can go and read about him

445
00:27:09 --> 00:27:13
at the MIT website,
but this is Professor Davison.

446
00:27:13 --> 00:27:17
He is a colleague of mine in
inorganic chemistry,

447
00:27:17 --> 00:27:21
here at MIT.
He became an emeritus faculty

448
00:27:21 --> 00:27:25
member this past summer,
but his research career spanned

449
00:27:25 --> 00:27:30
40 years here at MIT.
He came in 1964.

450
00:27:30 --> 00:27:33
And he did research in a lot of
different areas of inorganic

451
00:27:33 --> 00:27:37
chemistry, and did not get into
technetium until 1980 because he

452
00:27:37 --> 00:27:41
struck up a collaboration with
the fellow at Harvard Medical

453
00:27:41 --> 00:27:43
School, who I will show you
next.

454
00:27:43 --> 00:27:46
He is a Welshman.
He got his Ph.D.

455
00:27:46 --> 00:27:49
with the Nobel Laureate
Geoffrey Wilkinson at Imperial

456
00:27:49 --> 00:27:52
College, London,
after Jeff Wilkinson was denied

457
00:27:52 --> 00:27:55
tenure by Harvard,
after which he got his Nobel

458
00:27:55 --> 00:27:57
Prize.
They did not make a very good

459
00:27:57 --> 00:28:01
choice, there.
But, in any event,

460
00:28:01 --> 00:28:05
Professor Davison learned and
became one of the top inorganic

461
00:28:05 --> 00:28:08
and organometallic chemists of
his generation.

462
00:28:08 --> 00:28:11
And, in fact,
he is now a Fellow of the Royal

463
00:28:11 --> 00:28:14
Society, which is quite a
special distinction.

464
00:28:14 --> 00:28:17
I went over there for the
ceremony in London when he was

465
00:28:17 --> 00:28:20
being inducted into the Royal
Society.

466
00:28:20 --> 00:28:24
And they pull out the book that
is signed by all the new

467
00:28:24 --> 00:28:26
inductees into the Royal
Society.

468
00:28:26 --> 00:28:30
And one of the early signatures
in the book is that of Isaac

469
00:28:30 --> 00:28:33
Newton.
So he signed the same book as

470
00:28:33 --> 00:28:36
Isaac Newton.
You have to make sure your hand

471
00:28:36 --> 00:28:39
does not tremble and blot the
page.

472
00:28:39 --> 00:28:42
It would be a big problem.
They actually go ahead and

473
00:28:42 --> 00:28:47
teach them how to sign the book
and practice in advance because

474
00:28:47 --> 00:28:51
they use a quill pen dipped into
ink, just the way Isaac Newton

475
00:28:51 --> 00:28:53
did it.
And this coming spring,

476
00:28:53 --> 00:28:57
Professor Davison is going to
Atlanta, as many of us chemists

477
00:28:57 --> 00:29:02
are, for the American Chemical
Society meeting there.

478
00:29:02 --> 00:29:04
But he is going for a special
reason.

479
00:29:04 --> 00:29:07
He is winning the American
Chemical Society Award for

480
00:29:07 --> 00:29:10
Creative Invention,
which is a very prestigious

481
00:29:10 --> 00:29:12
award.
And I believe he is the first

482
00:29:12 --> 00:29:16
from our department ever to win
the Award for Creative

483
00:29:16 --> 00:29:18
Invention.
And that can go to a person in

484
00:29:18 --> 00:29:20
any area of chemistry,
in fact.

485
00:29:20 --> 00:29:24
That is a really nice thing.
And Professor Davison was a

486
00:29:24 --> 00:29:27
great mentor of both
undergraduate and graduate

487
00:29:27 --> 00:29:31
students here at MIT over the
years.

488
00:29:31 --> 00:29:35
And next let me show you that
it takes not one Welshman,

489
00:29:35 --> 00:29:39
but two, to make a drug.
And here is the other one,

490
00:29:39 --> 00:29:43
Alan Jones, a very good
personal friend of Alan Davison.

491
00:29:43 --> 00:29:48
He and Alan got together in the
early `80s to see if they might

492
00:29:48 --> 00:29:53
not be able to bring inorganic
chemistry and coordination

493
00:29:53 --> 00:29:57
chemistry to nuclear medicine in
order to develop a diagnostic

494
00:29:57 --> 00:30:01
imaging agent.
They got together,

495
00:30:01 --> 00:30:04
and their research was
extremely successful.

496
00:30:04 --> 00:30:08
And they have done research in
other areas, too,

497
00:30:08 --> 00:30:12
together over the years.
And their students go back and

498
00:30:12 --> 00:30:17
forth between the labs here and
Building 6 at MIT and over at

499
00:30:17 --> 00:30:22
Harvard Medical School to do the
different kinds of studies that

500
00:30:22 --> 00:30:24
they do.
It turns out that his

501
00:30:24 --> 00:30:28
chemistry, making these
six-coordinate complexes of

502
00:30:28 --> 00:30:31
technetium-1,
has led to the development of

503
00:30:31 --> 00:30:36
Cardiolite.
This now is called Sestamibi.

504
00:30:36 --> 00:30:41
That is an abbreviation for
this compound that has six of

505
00:30:41 --> 00:30:44
these isocyanide ligands on
technetium.

506
00:30:44 --> 00:30:48
When you see Sestamibi,
you will know what molecule

507
00:30:48 --> 00:30:51
that is.
It is the one that actually

508
00:30:51 --> 00:30:56
became commercial and was
approved by the FDA in 

509
00:30:56 --> 00:31:02
after extensive critical trials.
I will show you the structure

510
00:31:02 --> 00:31:06
in a moment, but it is a
variation on the t-butyl,

511
00:31:06 --> 00:31:11
where one of the methyl groups
is replaced with a methoxy

512
00:31:11 --> 00:31:14
group.
It is a methyl-ether species.

513
00:31:14 --> 00:31:19
And Cardiolite was originally
manufactured and brought into

514
00:31:19 --> 00:31:23
being by DuPont Merck.
And they sold it later to

515
00:31:23 --> 00:31:27
Bristol-Meyers Squibb.
And so you will see that

516
00:31:27 --> 00:31:32
Bristol-Meyers Squibb has a
section devoted to medical

517
00:31:32 --> 00:31:36
imaging.
And this drug that was the

518
00:31:36 --> 00:31:41
brainchild of Davison and Jones
is currently the most widely

519
00:31:41 --> 00:31:46
used diagnostic imaging agent
for looking at myocardial

520
00:31:46 --> 00:31:49
perfusion.
It is used in heart imaging

521
00:31:49 --> 00:31:54
tests all around the world,
every day, so it is a very

522
00:31:54 --> 00:31:59
important molecule contributing
to the health and welfare of

523
00:31:59 --> 00:32:05
people all over the world.
And what you will see is there

524
00:32:05 --> 00:32:09
are here descriptions of the
stress tests that people take.

525
00:32:09 --> 00:32:12
Let's see.
Cardiolite imaging guide.

526
00:32:12 --> 00:32:16
You have education programs.
Let's just check out the

527
00:32:16 --> 00:32:20
imaging guide for a moment.
These companies have pretty

528
00:32:20 --> 00:32:25
good graphics on their websites.
And remember the doughnut I was

529
00:32:25 --> 00:32:29
showing you, there it is right
here.

530
00:32:29 --> 00:32:32
There are different ways to
look at the heart using

531
00:32:32 --> 00:32:37
Cardiolite to see if the blood
is perfusing the heart properly.

532
00:32:37 --> 00:32:41
That might be the short axis.
You can view the scan images.

533
00:32:41 --> 00:32:45
This is how a normal healthy
heart will differ when it has

534
00:32:45 --> 00:32:48
been stressed after exercise or
at rest.

535
00:32:48 --> 00:32:51
That is why they call these
stress tests.

536
00:32:51 --> 00:32:55
You are seeing how the blood is
distributed in the heart using

537
00:32:55 --> 00:33:00
the property of the radionuclide
technetium-99M.

538
00:33:00 --> 00:33:02
There is one.
That is a different one.

539
00:33:02 --> 00:33:05
I am not going to spend too
much time on this,

540
00:33:05 --> 00:33:09
but I am giving you the link to
this website so you can go and

541
00:33:09 --> 00:33:14
look at how people actually use
clinically technetium Sestamibi

542
00:33:14 --> 00:33:17
to image the heart.
I want to show you just a few

543
00:33:17 --> 00:33:20
other things here,
one of which is that,

544
00:33:20 --> 00:33:23
as you may be aware,
the same molecule can have

545
00:33:23 --> 00:33:28
different names if it is used
for different purposes.

546
00:33:28 --> 00:33:32
Cardiolite is one of the names
given to Sestamibi,

547
00:33:32 --> 00:33:36
but another name given to
Sestamibi, here it is,

548
00:33:36 --> 00:33:38
is Miraluma.
And Miraluma,

549
00:33:38 --> 00:33:41
it turns out,
is really quite useful at

550
00:33:41 --> 00:33:46
detecting breast cancer when
breast lesions are not readily

551
00:33:46 --> 00:33:49
visible using mammography or
ultrasound.

552
00:33:49 --> 00:33:54
If you go to this website and
look at the information for

553
00:33:54 --> 00:33:59
healthcare professionals,
as you all are sitting here,

554
00:33:59 --> 00:34:04
you will be able to see breast
tumors that are detected very

555
00:34:04 --> 00:34:09
nicely using Sestamibi that were
missed using ultrasound or

556
00:34:09 --> 00:34:13
mammography.
And you might like this.

557
00:34:13 --> 00:34:17
If you try to go into that
information, you're first

558
00:34:17 --> 00:34:21
confronted with a test.
And you have to pass the test

559
00:34:21 --> 00:34:26
and know that the risk of breast
cancer increases with age.

560
00:34:26 --> 00:34:30
If you get that right,
then you can go on and actually

561
00:34:30 --> 00:34:35
look at the images that are made
using this drug.

562
00:34:35 --> 00:34:39
Now, I also give you a link
here to the Cardiolite story

563
00:34:39 --> 00:34:43
that is a nice article written
in the MIT Undergraduate

564
00:34:43 --> 00:34:47
Research Journal about
Professors Davison and Jones,

565
00:34:47 --> 00:34:50
their students,
and the creation of this

566
00:34:50 --> 00:34:54
clinical tool.
You can go there and read that.

567
00:34:54 --> 00:34:56
And it has some more
information.

568
00:34:56 --> 00:35:00
And then, finally,
I do give you a link to

569
00:35:00 --> 00:35:03
Sestamibi.
You will probably be appalled

570
00:35:03 --> 00:35:07
at the way this website draws
the isocyanide complex of

571
00:35:07 --> 00:35:09
technetium.
We know very well that that is

572
00:35:09 --> 00:35:12
a linear bond angle at those
carbon atoms,

573
00:35:12 --> 00:35:15
not bent like that,
so that is not a very good

574
00:35:15 --> 00:35:18
representation in terms of
structural fidelity.

575
00:35:18 --> 00:35:22
But if you want to know which
isocyanide is used in vivo for

576
00:35:22 --> 00:35:24
imaging organs,
it is this one with the methoxy

577
00:35:24 --> 00:35:28
group, instead of one of the
methyl groups of the t-butyl

578
00:35:28 --> 00:35:31
group.
It is very similar to the

579
00:35:31 --> 00:35:36
original one that Mike Abrams
made first back in 1983 because

580
00:35:36 --> 00:35:40
they already had t-butyl
isocyanide around from other

581
00:35:40 --> 00:35:43
things.
It is a really remarkable

582
00:35:43 --> 00:35:47
story, a fantastic story.
And having told it to you,

583
00:35:47 --> 00:35:51
I am now going to have to do
something that I very much

584
00:35:51 --> 00:35:54
regret.
Now you can go on and sample

585
00:35:54 --> 00:36:00
all the other exciting chemistry
subjects at MIT in your future.

586
00:36:00 --> 00:36:04
I hope to interact with many of
you again in that context.

587
00:36:04 --> 00:36:08
And I wish you good luck.
I know that you all will do

588
00:36:08 --> 00:36:11
fantastic things.
Having said that,

589
00:36:11 --> 00:36:15
I am going to have to close the
book on this semester.

590
00:36:15.429 --> 36:18
[APPLAUSE]