NUCLEAR MEDICINE AND

NEUROSCIENCE

Medicina Nucleare – Università di Cagliari

 The clinical problem
CEREBRAL BLOOD FLOW
The study of cerebral blood flow (CBF) is relevant to the
clinical investigation of a large group of neurological and
psychiatric disturbances.
In normal man CBF varies between 50-60 ml/min/100g of
brain substance. The flow in normal gray matter is higher
(65 to 85 ml/min/100g) than in normal withe matter (27 to
33 ml/min/100g).
Normal cerebral function is still possible with CBF values
as low as 20 ml/min/100g, the brain compensating with an
increse in oxygen extraction from the circulation.
At 15 ml/min/100g critical ischaemia is reached and, if
prolonged, irreversible cellular damage will occur.
 CBF and clinical problem

• Transient ischaemic attack (TIA)

• Prolonged reversible ischaemia with neurological deficit
(PRIND)
• Stroke
• Focal epilepsy
• Trauma
• Migraine
• Dementia

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 Central Nervous System and
Nuclear Medicine Procedures

Single Photon Emission Computed Tomography

(SPECT)

Positron Emission Tomography

(PET)
 IDEAL BRAIN PERFUSION TRACER

• WOULD PASS IMMEDIATELY THROUGH THE LUNGS

• WOULD TRAVERSE THE BLOOD BRAIN BARRIER

• WOULD BE EXTRACTED COMPLETELY BY THE BRAIN

DURING THE FIRST PASS

• WOULD REMAIN IN PLACE WITHOUT REDISTRIBUTION

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 IDEAL BRAIN PERFUSION TRACER

• Lipophilicity The amines

First tracer : a precursor of Amphetamine (123I-IMP)

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 Radiopharmaceuticals for SPECT
cerebral perfusion studies
• Tc-hexamethylpropylene amine oxime
99m

(HMPAO)
neutral lipophilic complex

• Tc-ethyl cysteinate dimer

99m

(ECD)
neutral lipophilic complex
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 Cellular Basis of ECD Brain
Retention
• ECD crosses the blood-brain barrier
• Goes trough cell membranes because of its
lipophilic nature
• Is reteined intracellularly after its conversion to
hydrophilic form by esterase activity
• High membranar esterase activity will result in a
small intacellular ECD content
• High cytosolic esterase activity will favor ECD
retention
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 Cellular Basis of HMPAO Brain
Retention
• HMPAO crosses the blood-brain barrier
• Goes trough cell membranes because of its
lipophilic nature
• Is reteined intracellularly after its conversion to
hydrophilic form
• Intracellular lipophilic-hydrophilic conversion
has been related in part to the cellular
glutathione content
• The redox activity of the interstitial space is a
major determinant of HMPAO retention
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SPECT BRAIN IMAGES

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SPECT BRAIN IMAGES

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SPECT BRAIN IMAGES

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 Tc-HMPAO BRAIN SPECT
99m

CLASSICAL MIGRAINE
(asymptomatic phase)

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 Tc-HMPAO BRAIN SPECT
99m

CLASSICAL MIGRAINE
(aura phase)

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99m
Tc-HMPAO BRAIN SPECT
TENSION HEADACHE

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 ECD SPECT
sezione assiale : Normale

Medicina Nucleare - Università di Cagliari

 ECD BRAIN SPECT
sezione assiale

Wilson’s disease

Medicina Nu cle are -Unive rsità di Cagliari

 The clinical problem
MOVEMENT DISORDERS

• A common anatomic locus within the basal ganglia

• The balance between cholinergic and dopaminergic
neuronal activity is condition for normal motor
function
• Damage of dopaminergic nigrostriatal neurons is the
unifying neuropathology of PD and of various forms
of parkinsonism
• Dopamine plays a pivotal role in regulation and
control of movement
Fantoccio: caudato e putamen
SPECT ligands for neuroreceptors
• Muscarinic receptors
• Dopamine receptors
• Dopamine transporters
• Central benzodiazepine receptors
• N-methyl D-aspartate receptors
• Opioid receptors
• Somatostatin receptors
• Corticosteroid receptors
• Gonadal steroid receptors
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 The clinical problem
MOVEMENT DISORDERS

• Imaging studies in living brain with

radiotracers labeling dopamine receptors,
dopamine transporters or precursor of
dopamine
 Dopamine receptors

Five subtypes of dopamine receptors:

D1,D2 stimulate adenily cyclase

D3,D4,D5 inhibit adenily cyclase

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Dopamine D2 receptor SPECT
specific ligands

• 123
I-iodobenzamide (IBZM)
• 123
I-iodolisuride
• 123
I-2-spiperone

postsynaptic receptor markers

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 Dopamine transporter
• Membrane-bound protein that mediates
re-uptake of dopamine into presynaptic
nerve terminals
• A series of cocaine analogues have been
developed for SPECT imaging with very
high affinity to the dopamine transporter

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-Cagliari
 Dopamine transporter SPECT
ligands
• 123
I-ß-carbomethoxy- ß-iodophenyltropane (ß-CIT)
J Nucl Med 39:1500-1508, 1998

• 99m
Tc-tropane (TRODAT-1)
J Nucl Med 41: 584-589, 2000

presynaptic transporter marker

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99m
Tc-TRODAT-1 brain SPECT

trodat1.bmp trodat2.bmp
NORMAL PARKINSON’S DISEASE

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DATSCAN IMAGE
 GABA Receptors

γ-Aminobutyric acid (GABA) is the major

inhibitory neurotransmitter in the CNS. It
exerts an inibitory action in all forebrain
structures and may play a role in the
physiopathogenesis of certain neurological
conditions, including epilepsy.
GABA is syntetized in the presynaptic nerve
terminal and released upon stimulation. It
enters the synaptic cleft, where it interacts
with a receptor site on the postsynaptic cell
membrane. Two types of receptors (R) inhibit
the postsynaptic cell
Schematic of synapse with GABA receptor
GABA activates three different receptor
classes such as GABAA, GABAB and GABAC
receptors.
The GABAA are of great importance as they
play a pivotal role in the regulation of brain
excitability and many drugs such as
benzodiazepines and some anticonvulsivant
interact with these receptors so as to elicit
their pharmacological effects.
At the postsynaptic level, GABA mediates
both rapid inhibition through GABAA
receptors, wich are members of the ligand-
gated ion channel superfamily, and slow
inhibition through GABAB receptors, which
are members of G-protein-linked receptor
superfamily.
In both cases, GABA acts by increasing
membrane conductance for an ion having an
equilibrium potential near or more negative
than resting membrane potential. In this way,
the neuronal hyperpolarizes, thus preventing
cell firing.
In focal epilepsy a number of previous studies
have reported a decreased of GABAA
receptors in epileptic foci. These findings
may be related to the disinhibition
mechanism in GABA sistems underlying
epilepsy.
The GABAA receptor is composed of five
subunits, of wich there are four main classes:
α, β, γ, δ. Differences in subunit composition
are believed to determine the affinithy for
GABA and for other ligands that modulate
GABAA receptor function. Most GABAA
receptors bind benzodiazepine (BZD).
 BZD bind to the α subunit.
Iomazenil, a specific BZD antagonist, binds
reversibly to the most
BZD-GABAA receptors.
 Benzodiazepine receptor
ligands

• 123I-Iomazenil
• 11C-Flumazenil
 I-Iomazenil Brain SPECT
123

Abnormal vs Normal BZD receptor distribution

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 Tc-ECD vs 123I-IMZ brain SPECT and EEG
99m

IMZ

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