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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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00:12:01,000 --> 00:12:05,000
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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00:13:02,000 --> 00:13:05,000
some nice statements,
here.

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00:13:05,000 --> 00:13:08,000
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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00:13:11,000 --> 00:13:15,000
can be prepared directly from
TcO four minus with

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00:13:15,000 --> 00:13:19,000
the hope that such information
might lead to the development of

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new radiopharmaceutical agents
and/or to a better understanding

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00:13:22,000 --> 00:13:24,000
of the agents already in
clinical use.

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00:13:24,918 --> 00:33:03,000
This thesis was written in

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00:13:26,000 --> 00:13:30,000
Well, let me not get ahead of
myself here.

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00:13:30,000 --> 00:13:34,000
And let me just show you here
one of the first technetium

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complexes that Mike Abrams was
able to prepare.

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00:13:38,000 --> 00:13:42,000
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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00:13:47,000 --> 00:13:52,000
convert it into molecules that
are octahedral at technetium.

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00:13:52,000 --> 00:13:55,000
And, in fact,
most of the applications of

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technetium in nuclear medicine
do involve octahedral

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00:13:59,000 --> 00:14:03,000
six-coordinate technetium,
--

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00:14:03,000 --> 00:14:07,000
-- harkening back to what we
can understand based on the

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00:14:07,000 --> 00:14:10,000
efforts and achievements of
Alfred Werner.

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00:14:10,000 --> 00:14:13,000
Here is the octahedron,
pretty soon,

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00:14:13,000 --> 00:14:15,000
going to go into a patient's
body.

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00:14:15,000 --> 00:14:19,000
Here he has chosen to use
sulfur donor ligands,

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00:14:19,000 --> 00:14:21,000
these thiourea ligands in
making this.

234
00:14:21,000 --> 00:14:26,000
And he also made molecules in
which phosphines and phosphites

235
00:14:26,000 --> 00:14:31,000
were able to bind to technetium.
And later, as you will see,

236
00:14:31,000 --> 00:14:34,000
he also did work with
isocyanides.

237
00:15:00,000 --> 00:15:03,000
This is 90 degrees rotated.
Basically, the reason I am

238
00:15:03,000 --> 00:15:07,000
showing you this is that this is
a nuclear magnetic resonance

239
00:15:07,000 --> 00:15:09,000
spectrum of a technetium-99
compound.

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00:15:09,000 --> 00:15:12,000
Let me just explain that
initially, when doing these

241
00:15:12,000 --> 00:15:16,000
studies, Mike Abrams was working
mostly with technetium-99 that

242
00:15:16,000 --> 00:15:20,000
has the real long half-life so
you can actually make molecules

243
00:15:20,000 --> 00:15:25,000
on a scale sufficient for
isolation and purification.

244
00:15:25,000 --> 00:15:30,000
But then those methods would be
translated to working with the

245
00:15:30,000 --> 00:15:34,000
99M isotope.
And the difference between 99

246
00:15:34,000 --> 00:15:38,000
and 99M, has to do with the spin
of the nucleus.

247
00:15:38,000 --> 00:15:41,000
We have talked about electron
spin.

248
00:15:41,000 --> 00:15:46,000
Well, different nuclei have
themselves the property of spin.

249
00:15:46,000 --> 00:15:51,000
And technetium-99 has a spin
one-half nuclear spin.

250
00:15:51,000 --> 00:15:56,000
And then when it decays from
99M to 99, the 99 isotope has a

251
00:15:56,000 --> 00:16:00,000
spin nine-halves,
actually.

252
00:16:00,000 --> 00:16:04,000
And that is the lower energy
state that gives rise to this

253
00:16:04,000 --> 00:16:08,000
gamma photon emission.
And so, in the nuclear magnetic

254
00:16:08,000 --> 00:16:11,000
resonance spectrum,
observing the phosphorus 31

255
00:16:11,000 --> 00:16:15,000
nuclei that are connected to
this hexakisphosphate of

256
00:16:15,000 --> 00:16:18,000
technetium 1,
you see that there end up being

257
00:16:18,000 --> 00:16:22,000
ten lines.
And that is because of the spin

258
00:16:22,000 --> 00:16:27,000
nine-halves ground state of the
technetium-99 nucleus.

259
00:16:27,000 --> 00:16:30,000
You will see that back in the
`80s, we were looking at

260
00:16:30,000 --> 00:16:34,000
technetium-coupled phosphorus
NMR spectra, as well as,

261
00:16:34,000 --> 00:16:37,000
you saw X-ray crystallography a
moment ago.

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00:16:37,000 --> 00:16:41,000
This was real nice work.
And let's see what I have here.

263
00:16:41,000 --> 00:16:45,000
After Mike had successfully
synthesized some of these

264
00:16:45,000 --> 00:16:48,000
complexes they started
wondering, well,

265
00:16:48,000 --> 00:16:51,000
can we image organs with these.
The idea was that

266
00:16:51,000 --> 00:16:55,000
radiopharmaceuticals that had
been in use prior to this time

267
00:16:55,000 --> 00:17:00,000
did not really have ligands on
the metal.

268
00:17:00,000 --> 00:17:03,000
It was sort of the case that
they would take the metal in

269
00:17:03,000 --> 00:17:06,000
whatever form they got it off a
generator and just inject it

270
00:17:06,000 --> 00:17:09,000
directly into the patient.
And, in that case,

271
00:17:09,000 --> 00:17:12,000
you don't have an ability to
tune the properties of the metal

272
00:17:12,000 --> 00:17:16,000
to have it localize specifically
at organs that you might want to

273
00:17:16,000 --> 00:17:18,000
image.
And so they thought we are

274
00:17:18,000 --> 00:17:20,000
coordination chemists.
Let's put ligands on there,

275
00:17:20,000 --> 00:17:22,000
and you can use different
ligands.

276
00:17:22,000 --> 00:17:26,000
And then, the molecule will go
to different parts of the body

277
00:17:26,000 --> 00:17:29,000
specifically.
And, when we find the right

278
00:17:29,000 --> 00:17:32,000
ligand, we will be able to do
something useful,

279
00:17:32,000 --> 00:17:34,000
like image the heart.
And so here,

280
00:17:34,000 --> 00:17:38,000
they had an anesthetized dog
that they had injected with a

281
00:17:38,000 --> 00:17:41,000
solution of one of these
technetium complexes.

282
00:17:41,000 --> 00:17:44,000
This was a hexakis isobutyl
isocyanide technetium-99M.

283
00:17:44,000 --> 00:17:48,000
And they were able to show that
this stuff forms quantitatively,

284
00:17:48,000 --> 00:17:52,000
even at the tracer levels that
they are using to 10^-9 molar.

285
00:17:52,000 --> 00:17:56,000
Very dilute solutions.
And so you don't actually get

286
00:17:56,000 --> 00:18:00,000
much radioactivity put into you,
but because of the high energy

287
00:18:00,000 --> 00:18:04,000
nature of the gamma photons that
come out, you can easily image

288
00:18:04,000 --> 00:18:07,000
them with a gamma camera and you
can reconstruct the position

289
00:18:07,000 --> 00:18:10,000
from which that radiation is
originating.

290
00:18:10,000 --> 00:18:12,000
That is what allows you to
image an organ.

291
00:18:12,000 --> 00:18:15,000
And so here is a little
schematic of the ribcage of a

292
00:18:15,000 --> 00:18:17,000
dog.
And you can see that he is

293
00:18:17,000 --> 00:18:21,000
telling us where the liver is.
And then you are supposed to be

294
00:18:21,000 --> 00:18:25,000
able to see kind of a doughnut,
which is the myocardium of the

295
00:18:25,000 --> 00:18:28,000
heart here.
And you see it lighting up real

296
00:18:28,000 --> 00:18:30,000
nice, right here.
So right away,

297
00:18:30,000 --> 00:18:33,000
with one of the first complexes
that they made,

298
00:18:33,000 --> 00:18:37,000
they found that this stuff goes
shortly after injection and

299
00:18:37,000 --> 00:18:40,000
localizes in the heart and gives
you a pretty nice image of the

300
00:18:40,000 --> 00:18:42,000
heart.
And there are different

301
00:18:42,000 --> 00:18:46,000
viewpoints that you can take
when you image the heart using

302
00:18:46,000 --> 00:18:49,000
methods like this,
but this was already pretty

303
00:18:49,000 --> 00:18:52,000
exciting that one of the first
systems they made,

304
00:18:52,000 --> 00:18:55,000
these t-butyl groups on it,
were very nice imaging agents

305
00:18:55,000 --> 00:18:59,000
for a dog.
And then the basis for the

306
00:18:59,000 --> 00:19:03,000
nuclear cardiology application
of this chemistry is that if a

307
00:19:03,000 --> 00:19:07,000
person has had a heart attack or
is at-risk to suffer a heart

308
00:19:07,000 --> 00:19:10,000
attack, has some heart disease,
then what happens is you look

309
00:19:10,000 --> 00:19:14,000
at the heart and it doesn't
become very well-perfused with

310
00:19:14,000 --> 00:19:17,000
blood all the way around,
as it should in a normal

311
00:19:17,000 --> 00:19:20,000
healthy heart.
And so, if there is infarcted

312
00:19:20,000 --> 00:19:23,000
tissue, you see an image like
this, where part of the doughnut

313
00:19:23,000 --> 00:19:28,000
is not lighting up.
And that means that part of the

314
00:19:28,000 --> 00:19:31,000
heart is not getting suffused
with blood.

315
00:19:31,000 --> 00:19:35,000
And so this kind of diagnostic
test is called myocardial

316
00:19:35,000 --> 00:19:38,000
perfusion imaging,
because you are looking at how

317
00:19:38,000 --> 00:19:42,000
the heart is taking up blood in
all of its different parts

318
00:19:42,000 --> 00:19:46,000
because you can look at
different angles of view.

319
00:19:46,000 --> 00:19:50,000
And one also tends to do this
when the subject is at rest

320
00:19:50,000 --> 00:19:53,000
versus when the subject has been
stressed.

321
00:19:53,000 --> 00:19:57,000
So you will hear the term
stress test associated with this

322
00:19:57,000 --> 00:20:02,000
type of image.
And so this is really the first

323
00:20:02,000 --> 00:20:05,000
complex that Mike Abrams made
that they were actually testing

324
00:20:05,000 --> 00:20:08,000
in animals.
Here was an infarcted dog

325
00:20:08,000 --> 00:20:10,000
heart.
You see that there is blood not

326
00:20:10,000 --> 00:20:13,000
getting to this part of the
heart, up here.

327
00:20:13,000 --> 00:20:16,000
And this image was to be
compared with an image made

328
00:20:16,000 --> 00:20:20,000
using a different imaging agent
which was the state of the art

329
00:20:20,000 --> 00:20:23,000
at the time, here,
with just the first one.

330
00:20:23,000 --> 00:20:27,000
And there were so many choices
you could make of what ligand to

331
00:20:27,000 --> 00:20:32,000
put on this metal.
And the first one already works

332
00:20:32,000 --> 00:20:36,000
better than thallium-201 that is
inserted just as an aqueous

333
00:20:36,000 --> 00:20:38,000
solution.
So thallium-201 is also a

334
00:20:38,000 --> 00:20:41,000
popular isotope for applications
in nuclear medicine,

335
00:20:41,000 --> 00:20:44,000
but with technetium,
now, you have the ability to

336
00:20:44,000 --> 00:20:48,000
make coordination compounds
where the ligands are very

337
00:20:48,000 --> 00:20:50,000
tightly bonded to the metal
center.

338
00:20:50,000 --> 00:20:54,000
And then you can attach other
residues to this system by

339
00:20:54,000 --> 00:20:56,000
virtue of how you build the
ligands.

340
00:20:56,000 --> 00:21:01,000
That was really pretty amazing.
And then a few years later,

341
00:21:01,000 --> 00:21:04,000
also in the research group of
Alan Davison,

342
00:21:04,000 --> 00:21:09,000
Professor of Chemistry at MIT,
comes along one James Frederick

343
00:21:09,000 --> 00:21:11,000
Carnegie.
And what he decided to do for

344
00:21:11,000 --> 00:21:16,000
his thesis work was to go ahead
and actually make molecules like

345
00:21:16,000 --> 00:21:20,000
the ones that Mike Abrams made,
but to look at many different

346
00:21:20,000 --> 00:21:24,000
varieties with different
peripheral substituents because

347
00:21:24,000 --> 00:21:28,000
there are certain organic
functional groups that will be

348
00:21:28,000 --> 00:21:33,000
metabolized and chopped up by
enzymes in the body.

349
00:21:33,000 --> 00:21:36,000
These include ester groups,
for example.

350
00:21:36,000 --> 00:21:40,000
You can also attach to these
isocyanide ligands things that

351
00:21:40,000 --> 00:21:44,000
look like little proteins.
And you can see,

352
00:21:44,000 --> 00:21:47,000
then, how those react to being
injected.

353
00:21:47,000 --> 00:21:52,000
And so his goal here was really
to make something practical that

354
00:21:52,000 --> 00:21:56,000
would be useful as a
radiopharmaceutical for imaging

355
00:21:56,000 --> 00:22:00,000
organs.
And his discussion begins by

356
00:22:00,000 --> 00:22:04,000
just talking about the different
groups that he was going to

357
00:22:04,000 --> 00:22:08,000
append to the surface of his
coordination complex.

358
00:22:08,000 --> 00:22:12,000
And then, here is a little
synthesis slide from his thesis.

359
00:22:12,000 --> 00:22:15,000
Mike Abram's thesis,
the first one I showed you,

360
00:22:15,000 --> 00:22:19,000
was actually typed up by hand
on a typewriter.

361
00:22:19,000 --> 00:22:22,000
But Jim Carnegie's thesis was
prepared, he tells me,

362
00:22:22,000 --> 00:22:27,000
I was talking to him last night
about this, using a very

363
00:22:27,000 --> 00:22:31,000
primitive word processor.
One of the first-generation

364
00:22:31,000 --> 00:22:34,000
word processors.
Anyway, that is a little bit

365
00:22:34,000 --> 00:22:38,000
beside the point.
You just don't see as many nice

366
00:22:38,000 --> 00:22:42,000
graphics in these theses as you
do nowadays, but you do see a

367
00:22:42,000 --> 00:22:46,000
lot of beautiful chemistry.
Here is an isocyanide ligand.

368
00:22:46,000 --> 00:22:48,000
Look.
We have talked a lot about

369
00:22:48,000 --> 00:22:52,000
carbon monoxide in this class as
a ligand in its behavior to

370
00:22:52,000 --> 00:22:55,000
transition metals.
And so if you just change the

371
00:22:55,000 --> 00:23:00,000
oxygen of carbon monoxide into a
nitrogen, then you can have a

372
00:23:00,000 --> 00:23:04,000
substituent stuck to it.
Here is an example of an

373
00:23:04,000 --> 00:23:08,000
isocyanide ligand where the
metal is going to attach to the

374
00:23:08,000 --> 00:23:11,000
carbon.
And then, Carnegie decided to

375
00:23:11,000 --> 00:23:14,000
put other groups out here.
Here, he has a carboethoxy

376
00:23:14,000 --> 00:23:17,000
residue.
And the idea was that enzymes

377
00:23:17,000 --> 00:23:21,000
called esterases in the body can
clip off and metabolize the

378
00:23:21,000 --> 00:23:24,000
carboethoxy residue.
And what that will do is it

379
00:23:24,000 --> 00:23:28,000
will affect the way that the
technetium is bio-distributed in

380
00:23:28,000 --> 00:23:32,000
the body.
It will affect the kinetics of

381
00:23:32,000 --> 00:23:37,000
how long the technetium takes to
accumulate in an organ and how

382
00:23:37,000 --> 00:23:40,000
long it takes to then run out of
that organ.

383
00:23:40,000 --> 00:23:45,000
And also, he looked at examples
that have organic amide

384
00:23:45,000 --> 00:23:48,000
functional groups,
all connected to the

385
00:23:48,000 --> 00:23:51,000
isocyanide.
His thesis work was all about

386
00:23:51,000 --> 00:23:55,000
looking at different
isocyanides, six of them on

387
00:23:55,000 --> 00:23:59,000
technetium in the +1 oxidation
state.

388
00:23:59,000 --> 00:24:02,000
It is d^6 low-spin octahedral
diamagnetic systems.

389
00:24:02,000 --> 00:24:04,000
It talks here about the
radioactivity.

390
00:24:04,000 --> 00:24:08,000
It talks a little bit about the
technetium generator issue.

391
00:24:08,000 --> 00:24:11,000
It mentions that he is doing a
lot of this work in

392
00:24:11,000 --> 00:24:14,000
collaboration over at Harvard
Medical School.

393
00:24:14,000 --> 00:24:18,000
They had a lab over there where
they were cleared to use 99M.

394
00:24:18,000 --> 00:24:20,000
The 99 work was done here,
at MIT.

395
00:24:20,000 --> 00:24:24,000
And this was because of the
collaboration that I will tell

396
00:24:24,000 --> 00:24:27,000
you about shortly.
Here is one that I won't bother

397
00:24:27,000 --> 00:24:32,000
to turn over.
But this actually a pretty

398
00:24:32,000 --> 00:24:36,000
important slide.
You will get this pdf file from

399
00:24:36,000 --> 00:24:41,000
our website, but you will see
that he is taking pertechnetate

400
00:24:41,000 --> 00:24:44,000
and saline.
The key feature,

401
00:24:44,000 --> 00:24:49,000
here, is that this synthesis is
quantitative at these very low

402
00:24:49,000 --> 00:24:54,000
concentrations that are what
used for nuclear medicine.

403
00:24:54,000 --> 00:25:00,000
Now, I showed you that Mike
Abrams imaged part of a dog.

404
00:25:00,000 --> 00:25:03,000
And as they progressed toward
doing human studies,

405
00:25:03,000 --> 00:25:06,000
they also imaged the rabbit.
And in these early tests,

406
00:25:06,000 --> 00:25:09,000
you know, you have these
chemistry Ph.D.

407
00:25:09,000 --> 00:25:13,000
students who don't really know
which organ is which in a bunny.

408
00:25:13,000 --> 00:25:16,000
They had to get a diagram like
this, out so they would have a

409
00:25:16,000 --> 00:25:20,000
map, so that when they started
shooting these molecules into

410
00:25:20,000 --> 00:25:24,000
the bunny they would know which
organ they were seeing light up

411
00:25:24,000 --> 00:25:27,000
by the gamma camera.
And this does not hurt the

412
00:25:27,000 --> 00:25:31,000
bunny.
The bunny is anesthetized and

413
00:25:31,000 --> 00:25:33,000
does not know,
so this is a perfectly nice

414
00:25:33,000 --> 00:25:35,000
thing to do.
And this one,

415
00:25:35,000 --> 00:25:39,000
I think the bunny is oriented
this way, here is the liver.

416
00:25:39,000 --> 00:25:43,000
And resting atop the liver on
the diaphragm is the heart of

417
00:25:43,000 --> 00:25:46,000
the bunny right here.
He has a lot of different

418
00:25:46,000 --> 00:25:49,000
images.
These, in the digital thesis

419
00:25:49,000 --> 00:25:53,000
archive, are a little bit fuzzy.
If you want to see better

420
00:25:53,000 --> 00:25:58,000
images, you might want to refer
directly to the thesis.

421
00:25:58,000 --> 00:26:01,000
But you will see that what he
is doing here is he is looking

422
00:26:01,000 --> 00:26:05,000
as a function of time after
injection, just the intensity of

423
00:26:05,000 --> 00:26:08,000
the gamma counts from the liver,
from the kidney.

424
00:26:08,000 --> 00:26:11,000
Notice the heart starts out
real high, and then it clears as

425
00:26:11,000 --> 00:26:14,000
the blood moves on into the
kidney and the liver.

426
00:26:14,000 --> 00:26:18,000
And so you can actually take
these images as a function of

427
00:26:18,000 --> 00:26:21,000
time and see where the
technetium is going in this

428
00:26:21,000 --> 00:26:23,000
living bunny.
And I thought I would mention

429
00:26:23,000 --> 00:26:26,000
that.
But then, I thought I would

430
00:26:26,000 --> 00:26:30,000
also show you this picture.
I have seen this in the real

431
00:26:30,000 --> 00:26:32,000
hard copy thesis,
and it looks much better in

432
00:26:32,000 --> 00:26:35,000
terms of organs lighting up and
so forth.

433
00:26:35,000 --> 00:26:38,000
It is very fuzzy in this image
from Carnegie's Ph.D.

434
00:26:38,000 --> 00:26:39,000
thesis.
This, in fact,

435
00:26:39,000 --> 00:26:43,000
is Professor Alan Davison,
who was himself the first test

436
00:26:43,000 --> 00:26:46,000
subject for his technetium
radiopharmaceutical.

437
00:26:46,000 --> 00:26:49,000
He just couldn't wait to have
this stuff shot into him,

438
00:26:49,000 --> 00:26:53,000
so he could see what his organs
looked like when imaged with a

439
00:26:53,000 --> 00:26:55,000
gamma camera.
That is Professor Davison,

440
00:26:55,000 --> 00:27:00,000
first human test subject on his
own chemistry.

441
00:27:00,000 --> 00:27:04,000
That was pretty remarkable.
Let me tell you just a little

442
00:27:04,000 --> 00:27:09,000
bit more about Alan Davison.
You can go and read about him

443
00:27:09,000 --> 00:27:13,000
at the MIT website,
but this is Professor Davison.

444
00:27:13,000 --> 00:27:17,000
He is a colleague of mine in
inorganic chemistry,

445
00:27:17,000 --> 00:27:21,000
here at MIT.
He became an emeritus faculty

446
00:27:21,000 --> 00:27:25,000
member this past summer,
but his research career spanned

447
00:27:25,000 --> 00:27:30,000
40 years here at MIT.
He came in 1964.

448
00:27:30,000 --> 00:27:33,000
And he did research in a lot of
different areas of inorganic

449
00:27:33,000 --> 00:27:37,000
chemistry, and did not get into
technetium until 1980 because he

450
00:27:37,000 --> 00:27:41,000
struck up a collaboration with
the fellow at Harvard Medical

451
00:27:41,000 --> 00:27:43,000
School, who I will show you
next.

452
00:27:43,000 --> 00:27:46,000
He is a Welshman.
He got his Ph.D.

453
00:27:46,000 --> 00:27:49,000
with the Nobel Laureate
Geoffrey Wilkinson at Imperial

454
00:27:49,000 --> 00:27:52,000
College, London,
after Jeff Wilkinson was denied

455
00:27:52,000 --> 00:27:55,000
tenure by Harvard,
after which he got his Nobel

456
00:27:55,000 --> 00:27:57,000
Prize.
They did not make a very good

457
00:27:57,000 --> 00:28:01,000
choice, there.
But, in any event,

458
00:28:01,000 --> 00:28:05,000
Professor Davison learned and
became one of the top inorganic

459
00:28:05,000 --> 00:28:08,000
and organometallic chemists of
his generation.

460
00:28:08,000 --> 00:28:11,000
And, in fact,
he is now a Fellow of the Royal

461
00:28:11,000 --> 00:28:14,000
Society, which is quite a
special distinction.

462
00:28:14,000 --> 00:28:17,000
I went over there for the
ceremony in London when he was

463
00:28:17,000 --> 00:28:20,000
being inducted into the Royal
Society.

464
00:28:20,000 --> 00:28:24,000
And they pull out the book that
is signed by all the new

465
00:28:24,000 --> 00:28:26,000
inductees into the Royal
Society.

466
00:28:26,000 --> 00:28:30,000
And one of the early signatures
in the book is that of Isaac

467
00:28:30,000 --> 00:28:33,000
Newton.
So he signed the same book as

468
00:28:33,000 --> 00:28:36,000
Isaac Newton.
You have to make sure your hand

469
00:28:36,000 --> 00:28:39,000
does not tremble and blot the
page.

470
00:28:39,000 --> 00:28:42,000
It would be a big problem.
They actually go ahead and

471
00:28:42,000 --> 00:28:47,000
teach them how to sign the book
and practice in advance because

472
00:28:47,000 --> 00:28:51,000
they use a quill pen dipped into
ink, just the way Isaac Newton

473
00:28:51,000 --> 00:28:53,000
did it.
And this coming spring,

474
00:28:53,000 --> 00:28:57,000
Professor Davison is going to
Atlanta, as many of us chemists

475
00:28:57,000 --> 00:29:02,000
are, for the American Chemical
Society meeting there.

476
00:29:02,000 --> 00:29:04,000
But he is going for a special
reason.

477
00:29:04,000 --> 00:29:07,000
He is winning the American
Chemical Society Award for

478
00:29:07,000 --> 00:29:10,000
Creative Invention,
which is a very prestigious

479
00:29:10,000 --> 00:29:12,000
award.
And I believe he is the first

480
00:29:12,000 --> 00:29:16,000
from our department ever to win
the Award for Creative

481
00:29:16,000 --> 00:29:18,000
Invention.
And that can go to a person in

482
00:29:18,000 --> 00:29:20,000
any area of chemistry,
in fact.

483
00:29:20,000 --> 00:29:24,000
That is a really nice thing.
And Professor Davison was a

484
00:29:24,000 --> 00:29:27,000
great mentor of both
undergraduate and graduate

485
00:29:27,000 --> 00:29:31,000
students here at MIT over the
years.

486
00:29:31,000 --> 00:29:35,000
And next let me show you that
it takes not one Welshman,

487
00:29:35,000 --> 00:29:39,000
but two, to make a drug.
And here is the other one,

488
00:29:39,000 --> 00:29:43,000
Alan Jones, a very good
personal friend of Alan Davison.

489
00:29:43,000 --> 00:29:48,000
He and Alan got together in the
early `80s to see if they might

490
00:29:48,000 --> 00:29:53,000
not be able to bring inorganic
chemistry and coordination

491
00:29:53,000 --> 00:29:57,000
chemistry to nuclear medicine in
order to develop a diagnostic

492
00:29:57,000 --> 00:30:01,000
imaging agent.
They got together,

493
00:30:01,000 --> 00:30:04,000
and their research was
extremely successful.

494
00:30:04,000 --> 00:30:08,000
And they have done research in
other areas, too,

495
00:30:08,000 --> 00:30:12,000
together over the years.
And their students go back and

496
00:30:12,000 --> 00:30:17,000
forth between the labs here and
Building 6 at MIT and over at

497
00:30:17,000 --> 00:30:22,000
Harvard Medical School to do the
different kinds of studies that

498
00:30:22,000 --> 00:30:24,000
they do.
It turns out that his

499
00:30:24,000 --> 00:30:28,000
chemistry, making these
six-coordinate complexes of

500
00:30:28,000 --> 00:30:31,000
technetium-1,
has led to the development of

501
00:30:31,000 --> 00:30:36,000
Cardiolite.
This now is called Sestamibi.

502
00:30:36,000 --> 00:30:41,000
That is an abbreviation for
this compound that has six of

503
00:30:41,000 --> 00:30:44,000
these isocyanide ligands on
technetium.

504
00:30:44,000 --> 00:30:48,000
When you see Sestamibi,
you will know what molecule

505
00:30:48,000 --> 00:30:51,000
that is.
It is the one that actually

506
00:30:51,000 --> 00:30:56,000
became commercial and was
approved by the FDA in

507
00:30:56,000 --> 00:31:02,000
after extensive critical trials.
I will show you the structure

508
00:31:02,000 --> 00:31:06,000
in a moment, but it is a
variation on the t-butyl,

509
00:31:06,000 --> 00:31:11,000
where one of the methyl groups
is replaced with a methoxy

510
00:31:11,000 --> 00:31:14,000
group.
It is a methyl-ether species.

511
00:31:14,000 --> 00:31:19,000
And Cardiolite was originally
manufactured and brought into

512
00:31:19,000 --> 00:31:23,000
being by DuPont Merck.
And they sold it later to

513
00:31:23,000 --> 00:31:27,000
Bristol-Meyers Squibb.
And so you will see that

514
00:31:27,000 --> 00:31:32,000
Bristol-Meyers Squibb has a
section devoted to medical

515
00:31:32,000 --> 00:31:36,000
imaging.
And this drug that was the

516
00:31:36,000 --> 00:31:41,000
brainchild of Davison and Jones
is currently the most widely

517
00:31:41,000 --> 00:31:46,000
used diagnostic imaging agent
for looking at myocardial

518
00:31:46,000 --> 00:31:49,000
perfusion.
It is used in heart imaging

519
00:31:49,000 --> 00:31:54,000
tests all around the world,
every day, so it is a very

520
00:31:54,000 --> 00:31:59,000
important molecule contributing
to the health and welfare of

521
00:31:59,000 --> 00:32:05,000
people all over the world.
And what you will see is there

522
00:32:05,000 --> 00:32:09,000
are here descriptions of the
stress tests that people take.

523
00:32:09,000 --> 00:32:12,000
Let's see.
Cardiolite imaging guide.

524
00:32:12,000 --> 00:32:16,000
You have education programs.
Let's just check out the

525
00:32:16,000 --> 00:32:20,000
imaging guide for a moment.
These companies have pretty

526
00:32:20,000 --> 00:32:25,000
good graphics on their websites.
And remember the doughnut I was

527
00:32:25,000 --> 00:32:29,000
showing you, there it is right
here.

528
00:32:29,000 --> 00:32:32,000
There are different ways to
look at the heart using

529
00:32:32,000 --> 00:32:37,000
Cardiolite to see if the blood
is perfusing the heart properly.

530
00:32:37,000 --> 00:32:41,000
That might be the short axis.
You can view the scan images.

531
00:32:41,000 --> 00:32:45,000
This is how a normal healthy
heart will differ when it has

532
00:32:45,000 --> 00:32:48,000
been stressed after exercise or
at rest.

533
00:32:48,000 --> 00:32:51,000
That is why they call these
stress tests.

534
00:32:51,000 --> 00:32:55,000
You are seeing how the blood is
distributed in the heart using

535
00:32:55,000 --> 00:33:00,000
the property of the radionuclide
technetium-99M.

536
00:33:00,000 --> 00:33:02,000
There is one.
That is a different one.

537
00:33:02,000 --> 00:33:05,000
I am not going to spend too
much time on this,

538
00:33:05,000 --> 00:33:09,000
but I am giving you the link to
this website so you can go and

539
00:33:09,000 --> 00:33:14,000
look at how people actually use
clinically technetium Sestamibi

540
00:33:14,000 --> 00:33:17,000
to image the heart.
I want to show you just a few

541
00:33:17,000 --> 00:33:20,000
other things here,
one of which is that,

542
00:33:20,000 --> 00:33:23,000
as you may be aware,
the same molecule can have

543
00:33:23,000 --> 00:33:28,000
different names if it is used
for different purposes.

544
00:33:28,000 --> 00:33:32,000
Cardiolite is one of the names
given to Sestamibi,

545
00:33:32,000 --> 00:33:36,000
but another name given to
Sestamibi, here it is,

546
00:33:36,000 --> 00:33:38,000
is Miraluma.
And Miraluma,

547
00:33:38,000 --> 00:33:41,000
it turns out,
is really quite useful at

548
00:33:41,000 --> 00:33:46,000
detecting breast cancer when
breast lesions are not readily

549
00:33:46,000 --> 00:33:49,000
visible using mammography or
ultrasound.

550
00:33:49,000 --> 00:33:54,000
If you go to this website and
look at the information for

551
00:33:54,000 --> 00:33:59,000
healthcare professionals,
as you all are sitting here,

552
00:33:59,000 --> 00:34:04,000
you will be able to see breast
tumors that are detected very

553
00:34:04,000 --> 00:34:09,000
nicely using Sestamibi that were
missed using ultrasound or

554
00:34:09,000 --> 00:34:13,000
mammography.
And you might like this.

555
00:34:13,000 --> 00:34:17,000
If you try to go into that
information, you're first

556
00:34:17,000 --> 00:34:21,000
confronted with a test.
And you have to pass the test

557
00:34:21,000 --> 00:34:26,000
and know that the risk of breast
cancer increases with age.

558
00:34:26,000 --> 00:34:30,000
If you get that right,
then you can go on and actually

559
00:34:30,000 --> 00:34:35,000
look at the images that are made
using this drug.

560
00:34:35,000 --> 00:34:39,000
Now, I also give you a link
here to the Cardiolite story

561
00:34:39,000 --> 00:34:43,000
that is a nice article written
in the MIT Undergraduate

562
00:34:43,000 --> 00:34:47,000
Research Journal about
Professors Davison and Jones,

563
00:34:47,000 --> 00:34:50,000
their students,
and the creation of this

564
00:34:50,000 --> 00:34:54,000
clinical tool.
You can go there and read that.

565
00:34:54,000 --> 00:34:56,000
And it has some more
information.

566
00:34:56,000 --> 00:35:00,000
And then, finally,
I do give you a link to

567
00:35:00,000 --> 00:35:03,000
Sestamibi.
You will probably be appalled

568
00:35:03,000 --> 00:35:07,000
at the way this website draws
the isocyanide complex of

569
00:35:07,000 --> 00:35:09,000
technetium.
We know very well that that is

570
00:35:09,000 --> 00:35:12,000
a linear bond angle at those
carbon atoms,

571
00:35:12,000 --> 00:35:15,000
not bent like that,
so that is not a very good

572
00:35:15,000 --> 00:35:18,000
representation in terms of
structural fidelity.

573
00:35:18,000 --> 00:35:22,000
But if you want to know which
isocyanide is used in vivo for

574
00:35:22,000 --> 00:35:24,000
imaging organs,
it is this one with the methoxy

575
00:35:24,000 --> 00:35:28,000
group, instead of one of the
methyl groups of the t-butyl

576
00:35:28,000 --> 00:35:31,000
group.
It is very similar to the

577
00:35:31,000 --> 00:35:36,000
original one that Mike Abrams
made first back in 1983 because

578
00:35:36,000 --> 00:35:40,000
they already had t-butyl
isocyanide around from other

579
00:35:40,000 --> 00:35:43,000
things.
It is a really remarkable

580
00:35:43,000 --> 00:35:47,000
story, a fantastic story.
And having told it to you,

581
00:35:47,000 --> 00:35:51,000
I am now going to have to do
something that I very much

582
00:35:51,000 --> 00:35:54,000
regret.
Now you can go on and sample

583
00:35:54,000 --> 00:36:00,000
all the other exciting chemistry
subjects at MIT in your future.

584
00:36:00,000 --> 00:36:04,000
I hope to interact with many of
you again in that context.

585
00:36:04,000 --> 00:36:08,000
And I wish you good luck.
I know that you all will do

586
00:36:08,000 --> 00:36:11,000
fantastic things.
Having said that,

587
00:36:11,000 --> 00:36:15,000
I am going to have to close the
book on this semester.

588
00:36:15,429 --> 00:36:18,000
[APPLAUSE]