Nuclear Medicine Resources Manual

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CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

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5.3.5.6. Data processing and interpretation

This is similar to the metabolic study. Since the receptor study requires

detailed spatial and timing information, the use of specific analysis and image

fusion with an anatomically informative modality (e.g. MRI) is recommended.

5.3.5.7. Special notes for receptor imaging

(a) Neuroreceptors

Neuroreceptors are membrane bound proteins that bind to exogenously

administered agents in addition to endogenously released neurotransmitters.

There are two types of receptor:

(1) Those that are a part of the structure of the so-called ligand-gated

channels that directly affect membrane potential and ionic permeability;

(2) Those that act by affecting intracellular second messengers via G

proteins.

The benzodiazepine (g-aminobutyric acid (GABA)-benzodiazepine

complex) receptor is an example of a ligand-gated channel receptor and is part

of a pore in the cell membrane that operates as an ion channel for the transport

of chloride ions. Dopamine receptors are examples of the second type of

receptor, which modulate the levels of intracellular second messengers such as

cyclic adenosine monophosphate (CAMP).

(b) Ligands

Ligands for imaging are generally selected from agonists for, or against,

neuroreceptors. They have no pharmacological effects because of the very

small amounts administered. An ideal ligand for neuroreceptor imaging should

demonstrate:

(1) High extraction across the BBB with rapid clearance from the blood;

(2) A high affinity constant;

(3) High specificity for the site of interest;

(4) No or small metabolites;

(5) Appropriate kinetics of binding.

Slow clearance from the sites of interest compared with non-specific sites

of interaction is required for quantitation.

5.3. CENTRAL NERVOUS SYSTEM

221

In vivo PET imaging enables the quantitative measurement of the density

of a receptor and the affinity of a ligand by means of compartment analysis.

Quantitative analysis of receptor imaging is important for the interpretation of

images and for a better understanding of the mechanism of neuronal disorders.

The in vivo distribution of a radiolabelled ligand is time dependent. The

early distribution reflects the delivery of the ligand by the circulating blood.

The specific binding of the labelled ligand with the target receptor gradually

increases, to reach the maximum after a certain time lapse. Simultaneously, the

ligands are dissociated or the label is released from the receptors. The freed

substrates are then cleared from the brain by the blood. The dynamic

equilibrium varies according to the characteristics of the labelled ligands and

receptors. When the specific activity of the radiolabelled ligand is low, the

receptor is easily occupied by the labelled ligand. The labelled ligands that bind

to non-specific sites and remain in the blood may obscure the tracer activity

specifically bound to receptors. On the other hand, if the specific activity is very

high and the mass of injected ligands is small, most of the labelled ligands bind

to receptors occupying only a fraction of the receptors. As a result, the free

ligand pool remains nearly empty. Under such conditions, PET images

continue to reflect delivery of the ligand by circulating blood or its transport

across the BBB. Kinetics models permit the calculation of density (B

max

maximal binding capacity of receptor sites (pmol · g

–1

· mL

–1

)), affinity (1/K

where K

is the dissociation constant at equilibrium (nM)) and binding

potential (B

max

Many of the kinetic principles and models developed for PET have been

applied to the analysis of receptor imaging by SPECT.

(d) Imaging receptors and their clinical application

For details of the various receptors, Table 5.15 should be consulted.

(1) Dopamine receptors

Dopamine was found to be involved in Parkinson’s disease. This

finding led eventually to the treatment of the disease by administration of

the dopamine precursor, L-dopa. Many neurons secreting dopamine as a

neurotransmitter are located in the substantia nigra, the limbic cortex,

hippocampus, anteromedial frontal cortex and medial and lateral habenula.

The direct action of dopamine on neurons is inhibitory. Dopamine

receptors are classified into two groups, namely the D1 group (D1 and D5)

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and the D2 group (D2, D3 and D4). Imaging of D2 receptors, which are

located at the basal ganglia, has been investigated mainly in association

with schizophrenia, Huntington’s disease and pituitary adenomas. Imaging

of D1 receptors with

123

I-SCH23982, which distributes in the corpus

striatum, has also been studied.

(2) Benzodiazepine receptors

The use of benzodiazepines in clinical practice as anxiolytics, antiepi-

leptics and sedatives was successful, since the benzodiazepines potentiate and

prolong the synaptic actions of g-aminobutyric acid (GABA), the main

inhibitory neurotransmitter in the mammalian brain. Imaging of a benzodi

azepine receptor with

C-flumazenil and

123

I-IMZ, which are disseminated in

the cerebral cortex, basal ganglia and thalami, has been studied in relation to

neurological disorders such as epilepsy, anxiety, ethanol dependency,

Huntington’s disease, Parkinson’s disease and hepatic encephalopathy, as well

as strokes.

(3) Opiate receptors

Opiates have been recognized both for their effective relief of pain and

for their mood altering properties. Three major opiate receptor subtypes exist:

m-receptors, d-receptors and k-receptors. The m-receptors have a high affinity to

morphine and related compounds, while d-receptors have their highest affinity

to encephaline. The k-receptors are distinguished by their high affinity to

dymorphins and certain benzomorphan synthetic opioids. Although multiple

neurotransmitters and their receptors have been implicated in human epilepsy,

it has also been observed that interactions of endogenous opioids with the m-

opiate receptor can produce both proconvulsant and anticonvulsant effects.

Investigation of m-opiate receptor imaging with

C-carfentanil,

C-diprenor-

phine and

F-acetylcyclofoxy, which are distributed in the basal ganglia,

thalami, frontal cortex and temporoparietal cerebral cortex, can throw light on

epilepsy and addiction.

(4) Muscarinic acetylcholine receptors

The muscarinic acetylcholine receptors are present in the CNS,

myocardium, pancreas, salivary glands and intestinal smooth muscles. Autopsy

samples have shown that the concentration of muscarinic acetylcholine

receptor is altered in a number of neurological disorders such as Huntington’s

disease, Parkinson’s disease, Alzheimer’s disease and sleep disorders, although

5.3. CENTRAL NERVOUS SYSTEM

223

there are conflicting reports concerning the receptor concentration changes.

Imaging of the muscarinic acetylcholine receptor has been studied in patients

with neurological disorders.

(5) Serotonin receptors

Serotonergic innervations and serotonergic receptors are widespread in

the central and peripheral nervous systems, although little is known about the

role of serotonin in human health and disease. Animal studies and clinical

pharmacological investigations suggest that the serotonin system has an

important role in mental disorders. Serotonin brain receptors can be divided

into two subtypes on the basis of their affinities to serotonergic agonists and

antagonists:

—The 5-hydroxytryptamine-1 (5-HT1: 1A, 1B, 1C, 1D, 1P) receptor class

for those receptors displaying high affinity (dissociation constants in the

nanomolar range for serotonin).

—The 5-HT2 class displaying low affinity (micromolar range) for serotonin

but high affinity for selective serotonergic antagonists. Imaging of 5-HT2

receptors by [F-18] setoperone (which distributes in the striatum and

cerebral cortex) has been investigated in patients with neurological and

mental disorders.

(6) Dopa metabolism

Doperminergic neurons that project from the substantia nigra to the

striatum are known to be involved in the control of movement. Parkinson’s

disease is characterized by nigral cell loss that gives rise to a profound decline

in striatal dopamine levels. In the processes of dopamine metabolism, tyrosine

hydroxylase is the initial enzyme in the biosynthetic pathways. This enzyme

catalyzes the hydroxylation of tyrosine to form 3,4-dihydroxy-L-phenylalanine

(L-dopa) and is located in dopamine synthesizing neurons. L-dopa is

decarboxylated to dopamine by aromatic L-amino acid decarboxylase. The

highest concentration of this enzyme is present in the striatal dopaminergic

nerve endings. The conversion of tyrosine to L-dopa, and L-dopa to dopamine,

is followed by dopamine uptake within storage vesicles in the nerve terminals.

Imaging dopa metabolism with the L-dopa analogue 6-[F-18] fluoro-L-dopa

has been studied in Parkinson’s disease.

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(7) Monoamine oxidase enzyme activity

Upon nerve activation, dopamine stored in vesicles in the terminal is

released into the synaptic cleft. Monoamine oxidase located on the

mitochondria is responsible for the catabolism of dopamine. Monoamine

oxidase activity is related to psychiatric illness, and a number of intriguing

studies link low platelet monoamine oxidase activity to vulnerability to

psychiatric illness. Monoamine oxidase A and B, which are identified by their

substrate selectivity and their sensitivity to different inhibitors, are subtypes of

the enzyme. Monoamine oxidase A oxidizes 5-hydroxytryptaine and is

selectively inhibited by clorgyline. Monoamine oxidase B oxidizes benzylamine

and is selectively inhibited by L-deprenyl. Monoamine oxidase enzyme activity

imaging has been used in patients with Parkinson’s disease and Alzheimer’s

disease.

(8) Acetylcholine enzyme activity

In the cholinergic nervous system, acetylcholine released into the

synaptic cleft is catabolized by acetylcholine esterase, inhibiting the effect of

the neurotransmitters. Imaging of acetylcholine enzyme activity has been

utilized for the early diagnosis of Alzheimer’s disease.

(9) Neurotransporters

When an action potential reaches the nerve terminal, neurotransmitters

stored in vesicles in the terminal are released into the synaptic cleft. Trans

porters in the presynaptic neuron are also responsible for the control (re-

uptake) of the neurotransmitters. Imaging of the dopaminergic transporter and

acetylcholinergic transporter has been shown to be useful for the evaluation of

Parkinson’s and Alzheimer’s disease, respectively.

BIBLIOGRAPHY TO SECTION 5.3.5

DEY, H.M., et al., Human biodistribution and dosimetry of the SPECT benzodiazepine

receptor radioligand iodine-123 iomazenil, J. Nucl. Med. 35 (1994) 399–404.

ECKELMAN, W.C., et al., External imaging of cerebral muscarinic acetylcholine

receptors, Science 223 (1984) 291–292.

5.3. CENTRAL NERVOUS SYSTEM

225

IYO, M., et al., Measurement of acetylcholinesterase by positron emission tomography

in the brains of healthy controls and patients with Alzheimer’s disease, Lancet 349

(1997) 1805–1809.

KUHL, D.E., et al., In vivo mapping of cholinergic neurons in the human brain using

SPECT and IBVM, J. Nucl. Med. 35 (1994) 405–410.

KUNG, M.P., et al., [Tc-99m] TRODAT-1: A novel technetium-99m complex as a

dopamine transporter imaging agent, Eur. J. Nucl. Med. 24 (1997) 372–380.

LARSON, S.M., CHIRO, G.D., Comparative anatomo-functional imaging of two

neuroreceptors and glucose metabolism: A PET study performed in the living baboon,

J. Comput. Assist. Tomogr. 9 (1985) 676–681.

MOZLEY, P.D., et al., Biodistribution and dosimetry of iodine-123-IBF: A potent

radioligand for imaging the D2 dopamine receptors, J. Nucl. Med. 34 (1993) 1910–1917.

SAHA, G.B., MacINTYRE, W.J., GO, R.T., Radiopharmaceuticals for brain imaging,

Semin. Nucl. Med. 34 (1994) 324–329.

SEIBYL, J.P., et al., Dynamic SPECT imaging of dopamine D2 receptors in human

subjects with iodine-123-IBZM, J. Nucl. Med. 33 (1992) 1964–1971.

WAGNER, H.N., Jr., et al., Imaging dopamine receptors in the human brain by positron

tomography, Science 221 (1983) 1264–1266.

WONG, D.F., et al., Effects of age on dopamine and serotonin receptors measured by

positron tomography in the living human brain, Science 226 (1984) 1393–1396.

WONG, D.F., et al., Positron emission tomography reveals elevated D2 dopamine

receptors in drug-naïve schizophrenics, Science 234 (1986) 1558–1563.

5.3.6. Radionuclide cisternography

5.3.6.1. Principle

After intrathecal injection, sterilized, pyrogen-free radiotracers circulate

within the cerebrospinal fluid (CSF) from the lumbar level upwards to the

cranial portion of the subarachnoid space. The tracer then flows along the

convexity of the brain to the superior longitudinal sinus where it is absorbed

with the CSF via the arachnoid villi. The process can be followed by external

imaging devices.

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The purpose of this section is to assist nuclear medicine practitioners in

recommending, performing, interpreting and reporting the results of radionu

clide cisternography.

5.3.6.2. Clinical indications

Investigations of patients should be made for the following purposes:

(a) To detect and differentiate obstructive and non-obstructive hydro-

cephalus;

(b) To detect other abnormalities in the subarachnoid space;

hydrocephalus;

(d) To detect the site and severity of a CSF fistula or leakage.

Studies are contraindicated in patients with severe intracranial hyper-

tension, where there is a risk of brain herniation.

5.3.6.3. Radiopharmaceuticals

Both

99m

Tc and

111

In can be used to label DTPA. The labelled product

must pass a series of quality control processes on sterility and apyrogenicity to

ensure its safe intrathecal use. The common adult doses are 185–370 MBq (5–

mCi) for

99m

Tc-DTPA and 18.5–37 MBq (0.5–1 mCi) for

111

In-DTPA.

5.3.6.4. Protocols

The appropriate protocols are the following:

(a) The patient should be well informed about the procedure.

(b) Preparations should be made for a standard lumbar puncture (regarding

patient positioning, sterilization and anaesthesia).

nostril.

(d) A lumbar puncture using the finest needle possible (22-gauge or finer)

should be conducted.

(e) After measuring pressure and withdrawing samples of CSF, the tracer

should be injected slowly and steadily.

(f) The patient should lie in the supine position with no pillow under the

head, resting for four to six hours.

5.3. CENTRAL NERVOUS SYSTEM

227

(g) Images should be taken, swabs removed, counts from the well counter

recorded and results interpreted.

5.3.6.5. Acquisition setting

The following procedure is adopted:

(a) Radionuclide cisternography is usually undertaken in planar mode,

although SPECT can be performed.

(b) The images are taken at 1, 2, 3, 6, 24 and 48 (

111

In only) hours after

injection.

subarachnoid space is imaged.

(d) Multiple views (anterior, posterior, vertex and both lateral) of the head

are needed to better visualize cisterna.

5.3.6.6. Data processing and image interpretation

The flow of activity in the spinal subarachnoid space is fast and smooth. A

low activity segment is noted in the thoracic region due to a thickening of the

spinal cord. The activity reaches the basal cisterna after one to three hours, and

then enters the sylvian and interhemispheric fissures. The lateral views display

the cisterna magna, quadrigemina, interpeduncularis, suprasellar and pontis.

The distribution of activity on both sides is symmetrical in the anterior and

posterior views.

After 24 hours, activity is distributed around the convexity of the brain,

especially along the superior sagittal sinus. Most of the activity in the cisterna is

cleared or diminished in intensity.

If any sign of lateral ventricles appears on the image, then communicating

hydrocephalus, with normal pressure or obstructive in nature, is suspected.

Interruption or loss of symmetry may indicate blockage of the CSF pathway.

Leakage or fistula is diagnosed if any activity is dispersed outside the

outline of the subarachnoid space. Counting each swab from the nose cavity

might help to locate the leak. To facilitate detection, the patient should lie

sitting with the head in hyperflexion.

5.3.6.7. Precautions

The radiopharmaceutical must meet all quality requirements for

intrathecal use. Two to three millilitres of 10% dextrose solution may be added

to help injection.

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5.4. NEPHROLOGY AND UROLOGY

5.4.1. Introduction

Renal radionuclide studies are commonly used procedures, particularly in

paediatrics. The goal is to obtain reliable functional and structural information

in a non-invasive way and to provide the clinician with both diagnostic and

prognostic information.

5.4.1.1. Paediatric considerations

Nuclear medicine techniques are essential in the initial diagnosis and

follow-up of many genito-urinary diseases in children, such as urinary tract

infection (UTI), neonatal hydronephrosis and vesicoureteral reflux.

Renal function parameters such as GFR and renal plasma flow (RPF) are

low in newborns; there is an increase in GFR from approximately 30 mL·min

–1

per 1.73 m

body surface area at birth to a nearly adult value by two years of

age. The tubules are even less mature than the glomeruli at birth, but

maturation of the tubules is more rapid. Renal immaturity in neonates reduces

to some extent the utility of radionuclide studies during the first months of life.

In infants, the relatively large extravascular space gives a low plasma

concentration of any freely diffusible injected substance. This, together with

renal immaturity, explains why

99m

Tc-DTPA scintigraphy in neonates is charac-

terized by poor visualization of the kidneys, high background activity with low

signal-to-noise ratio yet a rapid kidney transit time.

Using

99m

Tc-mercaptoacetyltriglycine (MAG3), the high protein binding

(90%) ensures a high plasma concentration and a low extravascular distri

bution space. This, coupled with the greater extraction efficiency of

99m

Tc-

MAG3 compared with that of

99m

Tc-DTPA, results in better renal delineation

and a higher signal-to-noise ratio. Technetium-99m MAG3 is therefore the

radiopharmaceutical of choice for dynamic renal studies in children, particu

larly below the age of two. High quality dynamic renal scans can be obtained

with

99m

Tc-MAG3 from 2 to 4 weeks of age.

In paediatric studies, the dose of radiopharmaceuticals has to be scaled

down. Table 5.16 suggests the fraction of the adult dose to be used in children.

For convenience, only the body weight (BW) of the child needs to be known.

The dose fraction is, however, based on body surface area.

5.4. NEPHROLOGY AND UROLOGY

229

5.4.2. Renal scintigraphy with

99m

Tc DMSA

5.4.2.1. Principle

The functional mass of the kidneys can be demonstrated by means of Tc-

99m dimercaptosuccinic acid (DMSA), a radiopharmaceutical that is taken up

by the proximal tubular cells of cortical and juxtamedullary nephrons after

extraction from the peritubular space and, to some extent, after filtration and

reabsorption. Technetium-99m DMSA is deposited in the proximal tubule and

is not released thereafter.

5.4.2.2. Clinical indications

Investigations with

99m

Tc-DMSA may be made for the following

purposes:

(a) Detection of renal scars in the follow-up of UTI in children;

(b) Detection of parenchymal involvement during acute febrile pyelo-

nephritis;

or a space occupying lesion;

TABLE 5.16. FRACTION OF ADULT DOSE USED FOR CHILDREN

BW (kg)

Fraction of

adult dose

BW (kg)

Fraction of

adult dose

BW (kg)

Fraction of

adult dose

3 0.10 22 0.50 42 0.78

4 0.14 24 0.53 44 0.80

6 0.19 26 0.56 46 0.82

8 0.23 28 0.58 48 0.85

10 0.27 30 0.62 50 0.88

12 0.32 32 0.65 52–54 0.90

14 0.36 34 0.68 56–58 0.92

16 0.40 36 0.71 60–62 0.96

18 0.44 38 0.73 64–66 0.98

20 0.46 40 0.76 68–70 0.99

BW, body weight.