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308 Nuclear Medicine Physics

neuropeptides. All these can be used to trigger vascular stress and thus, neu-

ronal metabolism. Under pathological conditions, in particular during the

development of brain ischemia, ﬂow-metabolism dissociation occurs. Rather

than showing the normal behavior described above, blood ﬂow changes may

not produce recognizable metabolism changes or trigger opposite metabolic

responses.

Once they arrive at the capillaries, the substrates or drugs then face cell

barriers separating blood from brain tissue. These cell barriers comprise

the capillary endothelium, a basement membrane, and astrocyte endfeet

(podocytes) amid a variable amount of interstitial liquid. These barriers are

explained next.

6.5.3.1 Barriers

The components of the CNS aredemarcated by three types of barriers that sep-

arate blood from the brain parenchyma with extracellular ﬂuid (blood–brain

barrier), blood from cerebrospinal ﬂuid (blood–cerebrospinal ﬂuid barrier),

and cerebrospinal ﬂuid from the brain parenchyma (brain–cerebrospinal ﬂuid

barrier). These barriers play an important role in the formation of images of

the CNS. Intrathecal administration (in the cerebrospinal ﬂuid of the spinal

cord subarachnoid space) of a myelography solute shows cerebrospinal ﬂuid

distribution and, hence, the state of the brain–cerebrospinal ﬂuid barrier.

This imaging method has been superseded by the tissue deﬁnition charac-

teristics of MRI, which enable an evaluation of the brain–cerebrospinal ﬂuid

interface with very good spatial resolution. However, MRI does not provide

information on cerebrospinal ﬂuid kinetics, especially on its production and

absorption. These can be better deﬁned by intravenous administration of

sodium pertechnetate (

99m

Tc), which diffuses from blood serum into intra-

ventricular space through choroid plexi (blood–cerebrospinal ﬂuid barrier,

i.e., production) and by intrathecal administration of, for instance, indium-

111- or technetium-99m-labeled DTPA, which, similar to cerebrospinal ﬂuid,

will be absorbed into blood through the arachnoid villi or arachnoid gran-

ulations and through the CNS and pia mater capillary walls. The other

barrier—the blood–brain barrier—is highly selective and regulates substrate

uptake. It therefore regulates the uptake of potentially useful radiopharma-

ceutical molecules for the investigation of physiopharmacological functions

and processes of the brain.

6.5.3.1.1 Blood–Brain Barrier

In the early twentieth century, Ehrlich [213,214] found out during his research

studies on chemotherapeutical agents that intravenous dye injection did not

cause any coloring in the brain, unlike all the other organs. Later, when study-

ing how various substances moved from blood into the brain and what effects

these substances had on the CNS, Stern and Gautier [215] realized that (1)

there was a barrier between the blood and the brain that excluded some

Imaging Methodologies 309

substances from the CNS and they called it the blood–brain barrier—barrière

hématoencéphalique; (2) substances unable to cross this barrier could not be

found in the cerebrospinal ﬂuid; and (3) some of the substances unable to

cross the barrier moved from the cerebrospinal ﬂuid to the CNS, for exam-

ple, iodine. Although not completely right, Stern and Gautier’s hypothesis

established for the ﬁrst time the selectivity feature of the blood–brain bar-

rier [217]. It still holds good today and is in many ways better understood.

The other very important feature of the blood–brain barrier, liposolubility,

was suspected by Becker and Quadbeck [218] and determined with the use

of quantitative analysis algorithms with deﬁned parameters for membrane

crossing (rate constants) [219,220].

The concept of blood–brain barrier was thus based on two physical-

chemical characteristics: selectivity and liposolubility. Although liposolubil-

ity is easy to understand and locate in cell membranes of capillary wall cells

(endothelial cells) and their adjacent cells (astrocytes), the barrier selectivity

is far more difﬁcult to anatomically ascribe. Some authors [221,222] con-

cluded that the endothelium was responsible for selectivity, whereas others

[223] noted that the endothelium was covered by a protoplasmic layer—the

podocytes—of astrocytes closely knitted by a basement membrane and that

there were no apparent gaps in these membranes [224]. The contact points

between two endothelial cells without gaps are called tight junctions and

are thereafter regarded as the structural location of the blood–brain barrier

according to Brightman and Reese [225]. These researchers showed that after

intraventricular injection, horseradish peroxidise diffuses through the inter-

stitial cell space around brain capillaries but cannot reach the bloodstream

and stops next to the tight junctions.

The blood–brain barrier [226] is permeable to liposoluble substances and is

apparently built of brain capillary endothelial cells, with their tight junctions.

Another of its properties is selectivity. Together, these two features explain

the results of many studies showing the absence of pharmacological effects

of nonlipophilic drugs on the CNS after intravenous administration. How-

ever, the same nonlipophilic, hydrosoluble drugs can cross the cerebrospinal

ﬂuid–brain barrier when given by intrathecal route and can cause measurable

pharmacological effects.

6.5.3.1.2 Structural Components of the Blood–Brain Barrier

The blood–brain barrier concept has been evolving a long time, and it is still

fundamentally based on the CNS capillary endothelial cells. Their functional

and morphological features are modulated by the astrocytes with which they

are in very close contact [227,228]. The endothelial cell layer has no gaps

as such. On the contrary, due to the intervention of astrocytes, there are

tight junctions, which build up a barrier that can only be crossed by means

of transport mechanisms in the cell barriers, without any type of passage

through pores. The modulation of the endothelial layer by glial cells was

shown by cross-experiments in which a nonvascular cell tissue transplanted

310 Nuclear Medicine Physics

into bird embryonic coeloms originated a blood–brain-type barrier [229]. On

the other hand, when coelomic tissue grafts were transplanted into embry-

onic brain tissue, capillaries were seen to have the same characteristics as

peripheral capillaries, that is, they had pores in the endothelial membranes

and there were no tight junctions. This was later conﬁrmed by Janzer and

Raff [230] when they showed that astrocytes are responsible for forming tight

junctions in nonneuronal tissue endothelial cells. To supplement these mod-

ulating and inducing capacities of astrocytes on endothelial cells, it was also

shown that these glial cells increase the frequency, size, and complexity of

tight junctions that are formed in cell growth media. Cultured endothelial

cells develop fragmented tight junctions of about 13 μm, whereas the size

of endothelial cells grown together with astroglia increases to approximately

165 μm.

Endothelial cells and astrocytes share yet another structure—the peri-

vascular basement membrane (BM)—which is composed of a ﬁbrous base-

ment sheet with high electron density inserted between two much less dense

electronic layers (one in contact with the endothelial cell membrane and the

other in contact with the astrocyte cell membrane) The basement sheet con-

tained glycoproteins, laminin, ﬁbronectin, variable amounts of different types

of collagen, and glycosaminoglycans [232].

This means that the blood–brain barrier should be thought of as a phys-

iological barrier composed of three structures: endothelial cells with tight

junctions, a perivascular basement membrane, and astroglia (astrocytes).

These three components of the blood–brain barrier make it selective and,

according to Crone [233], show well-deﬁned physiological features, which

are as follows:

1. It is a cell layer ensheathed by a continuous basement membrane

2. Endothelial cells are connected to one another by tight junctions

3. Permeability to hydrophilic substances (nonelectrolytes) is very low

4. Ionic permeability is very low

5. Water conduction is very low

6. Passive permeability to solutes is mainly through intercellular junc-

tions

7. It has facilitated transport mechanisms for some organic solutions

8. It shows stereospeciﬁcity is saturable and allows competitive inter-

actions

9. It has induction mechanisms

10. It has high electric resistance (∼2000 cm

) [234]

11. Its permeability is increased by high osmolarity levels

12. Na

–K

pumps are located on the abluminal membrane of endo-

thelial cells

Imaging Methodologies 311

All these characteristics help one way or the other to deﬁne the most suitable

transport mechanism for each substance or substrate present at the blood–

brain barrier during regional blood ﬂow distribution [235]. For instance, it is

increasingly accepted that endothelial cells are active in both the regulation

of brain extracellular ﬂuid components and the brain’s amino-acid content

[236]. Active amino-acid transport occurs on the abluminal membrane, the

facilitated transport of other amino acids is regulated on the luminal side, and

the neutral and long amino acids cross the barrier via mechanisms located on

the two sides of the endothelium [236].

6.5.3.1.3 Transport Mechanisms

Intracerebral radiopharmaceutical uptake is governed by the same properties

as solute uptake, which is primarily determined by the nonionized and, there-

fore, lipophilic fraction of each of the components in question. The product

uptakeand its relationto thecirculatingportion not taken up can be quantiﬁed

by the indicator diffusion technique. According to Crone [237], permeability

across the blood–brain barrier is given by the following formula:

P =−

ln(1 −E), (6.73)

in which P is the permeability or partition coefﬁcient, F is the blood or plasma

ﬂow, S is the capillary surface area, and E is the initial extraction fraction of

the substance in question.

6.5.3.1.3.1 Inﬂuence of Liposolubility or Lipophilicity Although the ﬁrst con-

tact and limitation to the passage of solutes from the blood to the CNS is the

endothelialcellmembrane, dueto itspropertiesoflipophilicity and selectivity,

the blood–brain barrier is not fully impervious to water and polar solutions.

Apparently, water and some low molecular weight polar solutions can pass

through hydrocarbon chains in cell membrane lipid bilayers. Further, the

tight junction dynamics is such that in some cases a small percentage of them

may open and allow the nonselective crossing of small ions [238]. According

to Equation 6.73, during the ﬁrst passage through the blood–brain barrier,

the higher the permeability (partition coefﬁcient), the higher the amount of

substance taken up by the CNS. As the (endothelial) capillary permeability

increases, the amount of substance crossing the blood–brain barrier depends

more and more on regional blood ﬂow, to the extent that in a theoretical

situation of maximum possible lipid solubility, the CNS uptake is linearly cor-

related with brain ﬂow, as shown by Equation 6.74, which deﬁnes diffusion

ability [237,239]:

= Q ln(1 −E), (6.74)

in which P

is ability to diffuse through the barrier, that is, the permeabil-

ity surface product, Q is cerebral blood ﬂow, and E is substance extraction.

312 Nuclear Medicine Physics

0.5

0.2

432

Q – blood flow (mL

· g

–1

· min

–1

)

PS (mL

· g

–1

· min

–1

)

Q.E (mL · g

–1

· min

–1

)

FIGURE 6.41

Theoretical curves based on Equation 6.74, also called the Crone–Renkin equation, in which

product ﬂow by extraction (Q.E) is compared with blood ﬂow (Q). Q.E represents blood volume

at any time (minute) at the barrier, and it is directly proportional to substance ﬂow or the amount

entering the brain per minute. Given that the equation assumes that back-diffusion is zero, the

Q.E product is also proportional to unidirectional substance ﬂow from blood to brain through

the blood–brain barrier.

The graph in Figure 6.41, modiﬁed from Bradbury [240], shows the relation

between cerebral blood ﬂow and blood extraction into cerebral tissue for

different P

values.

Considering that the endothelial capillary surface is linear and that there

is no back-diffusion from the brain back to the blood, the brain uptake of

a given compound is not signiﬁcantly affected by blood ﬂow when this is

higher than 0.5 mL g

−1

min

−1

and the P

is lower than 0.2 mL g

−1

min

−1

However, for P

of5mLg

−1

min

−1

or higher (meaning high extraction and

lipid solubility), brain uptake is chieﬂy determined by blood ﬂow, and so it

can be said that brain uptake is limited by regional cerebral blood ﬂow. Con-

sequently, this high liposolubility property has been used as the key factor

in the development of radiopharmaceuticals for brain function studies, espe-

cially of regional blood ﬂow, for example,

123

I-labeled iodoantipyrine and

Krypton. Another example of high liposolubility is

133

Xenon. In this case,

there is overt back-diffusion through the barrier, because is neither metabo-

lized in tissues nor does it bind to any cell structure unless its concentration

in blood is the same as or higher than in the brain. After peak concentra-

tion (for the dose administered) is achieved in the brain, if there is no arterial

input of

133

Xenon all molecules entering the bloodstream will be taken down-

stream (from arteries to veins) in proportion to regional capillary blood ﬂow

(washout rate).

Imaging Methodologies 313

6.5.3.1.3.2 Inﬂuence of Osmolarity or Osmotic Pressure For the examples of

interest in this chapter, osmolarity explains the movement of water molecules

through the blood–brain barrier. The P

of the blood–brain barrier is hard to

determine, even for radionuclide-labeled water.Water diffusioninto the brain

and from there to the bloodstream is partially dependent on blood ﬂow and

is totally dependent on it for relatively low ﬂow levels [241]. Paulson et al.

[242] calculated ﬁltration coefﬁcient or rate values (i.e., membrane osmotic

permeability) higher than the diffusion permeability rate, with a 4:3 ratio. This

led them to conclude that any osmotic pressure gradients across the blood–

brain barrier are higher than potential hydrostatic pressure gradients. Any

initial water ﬁltration due to hydrostatic pressure will be immediately limited

byan osmoticgradient ofhigher value and in theopposite direction.However,

if for any reason there is a rupture in the blood–brain barrier, ﬁltration of

substances from the plasma to cerebral tissues (interstitial space) is possible,

with or without proteins. This is most likely the mechanism underlying so-

called vasogenic cerebral edema.

6.5.3.1.3.3 Inﬂuence of Binding to Plasma Proteins Binding to plasma proteins

signiﬁcantly inﬂuences pharmacokinetics and interaction between pharma-

ceuticals and substances in the bloodstream. Free and plasma protein-bound

states are consideredto have a signiﬁcant inﬂuence on brain uptake. However,

some authors still disregard this, even in relatively recent studies. In general,

the drug’s lipophilic portion readily crosses the blood–brain barrier, whereas

nonlipophilic molecules stay in the bloodstream to be excreted or deposited

in tissues or organs other than the brain. Besides this, the amount of the

plasma protein-bound fraction also directly inﬂuences the passage through

the blood–brain barrier. This is further complicated by the type of bond, that

is, reversible or irreversible. A reversible bond introduces an important vari-

able in the amount of drug available to cross the barrier (free fraction), which

changes according to the free and protein-bound fraction concentration. In an

irreversible bond, the concentration of the free fraction available to cross the

barriers is constant.

However, there are some exceptions to this rule that are not fully under-

stood. Despite having signiﬁcant serum protein-bound fractions, the steroid

hormones

H-progesterone and

H-testosterone show brain uptake percent-

ages of between 80% and 100%, regardless of their serum protein-bound

fraction concentration [243]. Another example is tryptophan, 90% of which

is bound to plasma albumin. However, brain uptake after intracarotid bolus

injection of

C-tryptophan is not inﬂuenced by the presence of albumin [244].

Seemingly, tryptophanwas separated, as though sucked, fromits bindingpro-

tein (albumin) during the ﬁrst passage through the cerebral capillary. Three

mechanisms can be suggested to explain this:

1. Fast albumin dissociation due to strong brain uptake, with a conse-

quent very fast reduction in the free fraction.

314 Nuclear Medicine Physics

2. Differential changes in local physiological pH.

3. Metabolite displacement possibly due to antagonism, which can

change the association constant of the tryptophan–albumin complex.

The exact mechanism is still unknown. Nevertheless, it seems that the disso-

ciation constant for the tryptophan–albumin complex is signiﬁcantly higher

than the dissociation constant measured in vitro [245].

In fact, the explanation for both this event and what happens with thy-

roid hormones, which is similar, is still unclear. Thyroid hormones are polar

compounds, but they enter the brain by a speciﬁc transport mechanism

[246]. However, hormones are still introduced into cerebral capillaries with

their serum protein-bound fraction. The hormones are disconnected from the

proteins within capillaries by mechanisms that are also still unknown.

6.5.3.1.3.4 Other Inﬂuences Binding to erythrocytes (red blood cells) and

endothelial sequestration can similarly reduce the brain uptake rate of

lipophilic compounds.

Washout of molecules from the brain into the bloodstream and its rate of

change are different from what occurs in extracerebral tissues. Here, high

molecular weight molecules or suspended particles that cannot cross the cap-

illary endothelial barrier from the interstitial ﬂuid to blood are removed by

lymphatic drainage. In the brain, washout of even low molecular weight polar

solutes is difﬁcult. These cannot cross the blood–brain barrier from the inter-

stitial tissue to blood unless there is a speciﬁc transport mechanism through

the endothelium. Nonetheless, there are nonspeciﬁc removal mechanisms for

several polar solutes (nonlipophilic) that slowly penetrate the interstice, such

S-sulphate and

C-inulin. There are three, nonmutually exclusive mech-

anisms [247] to explain the existence of convection in washout of polar solutes

from the brain interstice to blood:

1. Secretion of interstitial ﬂuid through the capillaries to the blood

2. Circulation through perivascular spaces

3. Wave movements, particularly in arterial spaces

6.5.3.1.3.5 Speciﬁc Transport within the Blood–Brain Barrier If lipophilicity

were the only determining feature of the blood–brain barrier crossing rate to

enter cerebral tissues, then the brain would be deprived of adequate amounts

of several substrates it needs to survive, such as glucose and many amino

acids. Due to their relatively low partition ratio, these substrates cannot cross

the blood–brain barrier by simple (i.e., nonfacilitated) diffusion mechanisms.

Monosaccharides, carboxylic acids, neutral amino acids, dicarboxylic acids,

and some amines can cross the barrier with the help of active or facilitated,

speciﬁc transport mechanisms. These are stereospeciﬁc, saturable transport

mechanisms that can be inhibited by speciﬁc antagonists. They, therefore,

Imaging Methodologies 315

depend on energy expenditure. So, for example, monosaccharides have a

highly stereospeciﬁc transporter with high afﬁnity for

D-glucose. Peptides

are another example, presenting as large, polar molecules [248,249]. With-

out an appropriate, speciﬁc transport mechanism across the blood–brain

barrier, it would be impossible for peptides to play their important role in

neurotransmitter synthesis or to be neurotransmitters themselves (Table 6.2).

6.5.3.2 Factors Inﬂuencing Cerebral Capillary Permeability

Rather than being deﬁned by the permeability ratio, cerebral capillary per-

meability is usually deﬁned by the above mentioned P

product, because

the exact endothelial area by unit of cerebral tissue weight is unknown. Per-

meability to liposoluble (lipophilic) substances is primarily inﬂuenced by

regional cerebral blood ﬂow distribution and, of course, by the P

product.

Consequently, permeability increases with ﬂow, for instance, in hypercap-

nia and, thus, capillary vasodilatation and diminishes with regional cerebral

blood ﬂow reduction during hypocapnia, causing vasoconstriction [253]. Spe-

ciﬁc transport mechanisms, both facilitated and active, can be modulated by

a very variable number of factors [254–257], which change according to brain

tissue energy needs. Fasting [255] and porto-caval anastomosis [258] dramati-

cally change selective transporters in the blood–brain barrier, most likely due

to the marked metabolic changes they cause.

6.5.3.2.1 Importance to NM

The special selective permeability characteristic of the blood–brain barrier, in

particular its lipophilicity, prompted the research for development of radio-

ligands able to cross the barrier and show brain functions through uptake by

CNS cells. However, some radiopharmaceuticals that do not cross an intact

TABLE 6.2

Examples of Transport Systems through the Blood–Brain Barrier

Transport Michaelis

(Maximum Constant

Capacity) (V

max

) (Apparent)

Substance Type (Example) (μmols/g per min) (K

) (mM)

Monosaccharides [250] (D-glucose) 2–4 7–11

Monocarboxylic acids [251] (

L-lactate) 90 2

Neutral amino acids [251,252] (

L-leucine) 30–60 0.025–0.1

Basic amino acids [251] (

L-arginine) 8 0.09

Amines [251] (choline) 11 0.34

Nucleosides [251] (adenosine) 0.75 0.025

Purines [251] (adenine) 0.05 0.01

316 Nuclear Medicine Physics

blood–brain barrier are interesting for speciﬁc clinical applications, especially

in oncology and neurological infectology.

After intravenous injection, sodium pertechnetate (

99m

TcO

−

) presents at

the blood–brain barrier in its ionic form, hence it does not cross an intact

blood–brain barrier. However, it is secreted into cerebrospinal ﬂuid through

the choroid plexi (blood–cerebrospinal ﬂuid barrier), giving an idea of how

this barrier works in the blood–cerebrospinal ﬂuid direction. Sodium pertech-

netate was the ﬁrst radiopharmaceutical to mark an intact blood–brain barrier,

but negatively that is, by showing the normal brain as an empty image and

revealing uptake in areas of barrier disruption, as in cerebral infarction and

tumors, in which sodium pertechnetate accumulates in extracellular ﬂuid. Its

main disadvantage is choroid plexi visualization, which in less-experienced

hands can lead to false positive results. Therefore, whenever sodium pertech-

netate is needed, its use should be preceded by the secretion blockade of

choroid plexi, for instance, with sodium perchlorate. More recently, other

radiopharmaceuticals have been used (

99m

Tc-labeled glucoheptonate and

diethylene triamine pentaacetic acid) that arenot secreted by the choroid plexi

and, thus, do not need blocking drugs. Thallium chloride (

201

Tl) is another

example of a radiopharmaceutical that does not cross an intact blood–brain

barrier. In recent times, the clinical importance of these radiopharmaceuticals,

especially thallium chloride, has gained a new life, because they can be used

in the differential diagnosis of cerebral tumor recurrence and ﬁbrosis after

surgery and/or irradiation [259] and in the differential diagnosis between

infection (cerebral toxoplasmosis) and intracerebral lymphoma in patients

with viral immunodeﬁciency syndrome [260].

Thelipophilicity of the blood–brain barrierthat givesit selectivityprompted

the development of neutral and lipophilic compounds able to cross an intact

barrier. These compounds (radioligands) behave like chemical microspheres,

that is, they cross the endothelial-basement membrane-astrocyte barrier from

blood to brain to turn into polar compounds in the cerebral tissue, thus

becoming unable to cross the barrier in the opposite direction.

This causes intracerebral retention directly proportional to tin (

113

Sn)-

radiolabeled microsphere distribution in the capillary network (Figure 6.42)

and, thus, proportional to the regional cerebral blood ﬂow distribution.

This proportionality happens with highly varied levels of regional cere-

bral blood ﬂow. In the white matter (lower blood ﬂow levels), there is

apparently an inﬂation of ﬂow values by perfusion markers compared with

microspheres. The correlation is better in the usual ﬂow level range of gray

matter (the regression line shows a signiﬁcantly high correlation coefﬁcient,

r = 0.924).

These radiopharmaceuticals, generally called cerebral or regional cerebral

blood ﬂow perfusion markers (rCBF), have a clinical application with SPECT

to examine patients with cerebral ischemia and in the differential diagno-

sis of dementia, especially frontotemporal dementia and Alzheimer’s dis-

ease.

123

I-IMP (iodo-amphetamine),

99m

Tc-ECD (l, l-ethylcysteinate dimer),

Imaging Methodologies 317

200 400 600 800 1000 Bq/MB

Bq/MBqBq/MBq

113

Sn-Microspheres

113

Sn-Microspheres

99m

Tc-HMPAO

Gray matterWhite matter

00 100 200 300

200

y = 90.954 + 0.68211x

r = 0.924

y = 39.322 + 0.93719x

r = 0.885

400

600

800

1000

100

200

300

FIGURE 6.42

Comparison between distribution of a lipophilic cerebral blood ﬂow marker (

99m

Tc-hexa-

metazime) and distribution of

113

Sn-microspheres in white and gray matter samples from dog

brain (Adapted form D. C. Costa. A Study of the First

99m

Tc-labelled Radiopharmaceutical for the

Investigation of Cerebral Blood Flow in Man. PhD Thesis, University of London, 1989.)

99m

Tc–hexametazime, and

99m

Tc–HMPAO (hexa-methyl-propylene-amine-

oxime) are among the substances available on the market.

The physiological dynamics of cerebrospinal ﬂuid circulation is especially

well demonstrated by isotopic cisternography studies using

99m

Tc- o r

111

In-

labeled DTPA. After intrathecal injection (usually in the epidural space at the

lumbar spine level), the radiopharmaceutical is distributed by the cisternae

and eventually reabsorbed in the blood through the arachnoid villi or granu-

lations. At the moment, there is no other imaging technique that can show the

physiology of cerebrospinal ﬂuid distribution and reabsorption as innocu-

ously as isotopic cisternography. This technique serves not only to diagnose

hydrocephalus in the differential diagnosis of intracranial hypertension [262]

but also to predict the outcomes of potentially useful surgery.

The other clinical application of this isotopic cisternography technique,

screening for cerebrospinal ﬂuid loss [263], pertains to very ﬁne anatomical

resolution techniques, such as magnetic resonance. It is, however, still use-

ful in cases where magnetic resonance gives rise to false negative results.

However, more important is that the loss can be quantiﬁed with radio-

pharmaceuticals but not with magnetic resonance.

6.5.3.3 Neurotransmitters

In the CNS, brain, and beyond the blood–brain barrier, cell-to-cell, that is,

interneuronal, interaction and communication are central to all information

processing theories. The molecular neurobiology era, which has been grow-

ing for some years within neurosciences, is based on knowledge of neuronal

transmission and the role of neurotransmitter molecules in the many brain

functions. Neurotransmission requires the relevant neurotransmitters to be

ﬁrst synthesized at the presynaptic neuron and then transported to the neuron