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108 Nuclear Medicine Physics

mechanisms may occur to diminish the accumulation of deoxyglucose-6-

phosphate in tissue.

In cancer cells, there is usually an increase in the GLUT expression that

favors an increased uptake of glucose into the tissue. There arealso several key

enzymes in glycolysis that have their activity enhanced in tumor processes,

including hexokinase, the ﬁrst glycolytic enzyme. These two processes lead

to an increase in deoxyglucose uptake and consequent entrapment, which

provide the physiological basis for the widely successful use of [

F]FDG in

oncology.

4.8 SPECT Radionuclides

Currently,

99m

Tc is the most widely used diagnostic radionuclide and is

responsible for more than 80% of diagnostic scans done each year in hospitals

and clinics. However,a large number of other radioisotopes have found appli-

cation, both in diagnostics and in therapy [30–34]. Table 4.5 summarizes some

clinically used radionuclides, their physical characteristics, and their produc-

tion methods. The most important properties of a radionuclide to be used

in clinical applications are its half-life and decay mode, the energy of the

emitted radiation, and, at least as important, the cost and ease of its produc-

tion. Radionuclide half-lives should be long enough to allow production of

the corresponding radiopharmaceutical and to perform the diagnostic scan

but not so long as to increase the patient dosimetry without diagnostic ben-

eﬁts. Its energy should be appropriate for the detection system; for example,

for SPECT cameras the energy of the gamma rays should be between 100

and 250 keV. Outside this range, the images will have poor quality. For lower

energies, most of the photons will be stopped inside the patient’s body, result-

ing in poor statistics, while at the same time increasing the patient’s radiation

dose. At high energies, as a consequence of the low selectivity of the photons

TABLE 4.5

Physical Data for the Most Widely Used Nuclear Medicine Radionuclides and

Their Production Processes

Nuclide t

1/2

Main Emissions (keV) Production

Techenetium-99m 6.01 h γ 141 Generator (

Mo/

99m

Tc )

Iodine-123 13.2 h γ 159 Cyclotron (

124

Te(p, 2n)

123

Iodine-131 8.04 d γ 364, β 606 Nuclear ﬁssion

Thalium-201 73.1 h γ 167, 135; X68 −82

203

Tl(p,3n)

201

Pb →

201

Gallium-67 78.3 h γ 300, 181, 93 Cyclotron (

Zn(p, 2n)

Ga)

Indium-111 2.81 d γ 245, 171 Cyclotron

111

Cd(p,n)

111

Xenon-133 5.25 d γ 81; β 46; X 30–36 Nuclear ﬁssion

Krypton-81m 13.3 s γ 190 Generator (

Rb/

Kr)

Radiopharmaceuticals 109

by the collimator, there will be an increase in the scattering and, thus, a loss

of image quality.

Thedecay scheme is also a very importantcriterion to choosean appropriate

radionuclide: For therapeutic purposes, β

−

or α emission is desirable; whereas

for imaging diagnosis, particle emission is a big disadvantage, as it only con-

tributes to the absorbed radiation dose without providing any beneﬁt for the

imaging. A good example is

131

I, which decays by β

−

emission to an excited

nuclear state of

131

Xe, which, in turn, decays by emitting gamma radiation of

various energies, including 384, 637, 284, and 80 keV.

4.8.1 Technetium-99m: Production, Coordination Chemistry,

and Radiopharmaceuticals

In the Periodic Table of elements, technetium (Tc) is the element 43, a transition

metal. Its name comes from the Greek technetos, meaning artiﬁcial.

As indicated, technetium in the form of one of its isotopes (Tc-99m) is, by

far, the most widely used radioisotope in NM. This is due both to its excellent

nuclear properties and also to the fact that it can be produced in situ and daily

by a generator (see below).

Radionuclide generators are based on a relatively long-lived parent that

decays to a daughter nuclide, which is itself radioactive but with a short

half-life [72]. The system will be useful for routine applications only if there

is a straightforward method to separate the daughter radionuclide from its

parent. The most common generator system is the Mo-Tc-99m [73], which

is used daily in every NM Service around the world. However, there are

other generator systems, such as Rb-81/Kr-81m, Sr-82/Rb-82, and of growing

importance due to the increasing use of Ga-68 in PET imaging, the generator

system Ge-68/Ga-68 [75–77].

The commercial generator Mo-99/Tc-99m (Figure 4.8) contains radioactive

molybdate (sodium molybdate), adsorbed in an aluminum oxide column. The

99m

Tc, which is continuously formed inside the column, and the molybdate

have different chemical afﬁnities for the alumina, which allows their separa-

tion by column elution with saline solution. The reaction inside the column

follows the scheme:

MoO

−

(adsorbed in the column) →

99m

TcO

−

(free in solution) (4.3)

From consideration of the half-life ratio between

Mo (t

1/2

= 66 h) and

99m

Tc (t

1/2

= 6 h), we can easily conclude that this leads to a transient equilib-

rium, with the time or activity curves for the parent or daughter radionuclides

given by

[Mo]

= A

[Mo]

−λ

{Mo}

(4.4)

110 Nuclear Medicine Physics

Eluent

Eluted

Column

Lead

protection

FIGURE 4.8

Schematic representation of the

Mo-

99m

Tc generator.

[Tc ]

= A

[Mo]

[Tc ]

−λ

[Mo]

−λ

[Mo]

−e

−λ[Tc ]t

) +A

[Tc ]

−λ

[Tc ]

(4.5)

For the case where the initial technetium-99m activity equals zero (after one

elution), the above equations take the form:

[Tc ]

= A

[Mo]

[Tc ]

−λ

[Mo]

−λ

[Mo]

−e

−λ

[Tc ]

) (4.6)

The two curves involved can be represented by the diagram given in

Figure 4.9.

The upper curve for

99m

Tc corresponds to the direct application of these

equations; whereas the lower curve takes into account the fact that only 87%

of the decays produce 140 keV γ rays.

It is straightforward to demonstrate that the time at which the maximum

technetium activity is obtained corresponds to

[Tc ]

max



1.44

1/2[Mo]

1/2[Tc ]

1/2[Mo]

−t

1/2[Tc ]





1/2[Mo]

1/2[Tc ]



. (4.7)

This corresponds to ca. 22.8 h, which is the main reason that the

Mo–

99m

generators are normally eluted the same time each day to allow an almost

ideal accumulation of pertechnetate. Combining this process with the decay

scheme of the

99m

Tc permits determination of the conditions of maximum

activity in the presence of

Tc (Figure 4.10).

Radiopharmaceuticals 111

0.2

0.4

0.6

0.8

0 20406080100

Time (h)

99m

Activity

FIGURE 4.9

Activity/time diagrams for

Mo and

99m

Tc in the

Mo–

99m

Tc generator.

Tc-99m emits 140 keV γ rays with 89% abundance, which makes it almost

ideally suited for imaging with gamma cameras while being safe from the

pointof view ofthe radiation dose given to the patient. It has a veryconvenient

half-life of 6 h, which allows the preparation and quality control of the

99m

Tc-

radiopharmaceuticals and the possibility of performing even a complicated

imaging protocol.

The existence of lyophilized cold kits containing appropriate formulations

for

99m

Tc complexation makes it easy to obtain

99m

Tc radiopharmaceuticals

just by addition of

99m

Tc in the pertechnetate form (

99m

TcO

−

) to the kit.

The

99m

Tc is eluted from the generator as an aqueous solution of sodium

pertechnetate (Na

99m

TcO

) and has an oxidation number of +7. The

99m

is unreactive with most of the ligands and needs to be reduced. Tin chlo-

ride and HCl are among the most commonly used agents to reduce the

pertechnetate ion. After being reduced in the presence of suitable ligands,

the technetium bears an oxidation number ranging from +1 to +6, depend-

ing on the reductant and ligand characteristics and the coordination reaction

conditions.

Although the possibility that technetium can exist in all these oxidation

states may make it difﬁcult to control the reactions and also increases the

lability of the complexes formed, on the other hand, it does offer more pos-

sibilities for the modiﬁcation of the structure and properties of complexes

99m

66 h

6, 01 h

2, 12 × 10

years

Ru (stable)

99m

FIGURE 4.10

Production and decay scheme of

99m

Tc .

112 Nuclear Medicine Physics

through the choice of the appropriate ligands [35]. A further important char-

acteristic of these technetium compounds is the possibility of the presence of

isomeric structures: geometric isomers, epimers, enantiomers, and diasteri-

oisomers. The presence of isomers, which is more frequent with technetium

oxo-complexes, may have an important impact on the biological properties

of the radiopharmaceuticals, as these isomers often have differences in their

lipophilicity and, as a consequence, in their biodistribution proﬁle [35].

To sum up, technetium can produce a large number of complexes display-

ing different structures, oxidation states, with coordination numbers ranging

from 4 to 7, which introduces a very rich chemistry and a huge number of

synthetic pathways.

A large variety of

99m

Tc-radiopharmaceuticals have been developed and

approved by FDA for diagnosis, whereas a myriad of new ones are at the

preclinical phase. There is virtually no organ function or disease process, from

neuroreceptor imaging to oncology that cannot be visualized in NM using a

99m

Tc-based tracer [57]. Table 4.6 summarizes some of the new developments

in this area. For more information about

99m

Tc-based radiopharmaceuticals

and

99m

Tc chemistry, the readeris referred to excellent comprehensivereviews

and textbooks [31,35,36].

As with other metal-based radiopharmaceuticals,

99m

Tc radiopharma-

ceuticals can be classiﬁed in two categories: “technetium essential” and

“technetium tagged.” Technetium essential radiopharmaceuticals are those

in which the Tc is an integral part of the radiopharmaceutical and for which

the molecule would not be delivered to its target in the absence of the Tc. Their

in vivo behavior depends only on their chemical–physical properties, such as

size, charge, and lipophilic or hydrophilic character. The latter class, tech-

netium tagged radiopharmaceuticals, includes those in which the targeting

moiety (e.g., antibody, peptide, and hormone) has been labeled with

99m

Tc,

either directly or by using a bifunctional chelate; and their in vivo local-

ization is mediated by biological interactions with, for example, receptors

or proteins. A bifunctional chelator bears chelator groups that are able to

coordinate the metal, while, at the same time, having functional groups

which allow the radiopharmaceutical to be recognized by a target biologi-

cal molecule. The introduction of a chelator in a bioconjugated molecule can

have a profound effect on its biodistribution, and this will increase with a

decrease of the size of the biomolecule; this will be more pronounced for

small peptides than for larger antibodies. To minimize this effect, it is usual

to introduce a “spacer” to separate the chelator from the bioactive part of the

molecule [45].

Considering

99m

Tc compounds, we can include the following radiopharma-

ceuticals in the ﬁrst group (where their in vivo behavior depends only on the

complex structure):

99m

Tc-D,L-HM-PAO (Ceretec) and

99m

Tc-LL-ECD (

99m

coordinatedto N, N



-1,2-ethylenediylbis-L-cysteine diethyl ester—Neurolite),

both of which are used to determine brain–blood ﬂow; the complexes

99m

Tc-

DTPA and

99m

Tc-MAG3 (Technescan) used to evaluate kidney function; and

Radiopharmaceuticals 113

TABLE 4.6

Examples of

99m

Tc-Labeled Ligands as Diagnostic Radiopharmaceuticals

Radiopharmaceutical Chemical and Biological characteristics Application Reference

99m

Tc-TRODAT-1

99m

Tc complex in which a diaminodithiol ligand is complexed with the metal and a

tropane analog is derivatized from one nitrogen. It presents two diastereoisomers syn

on the coordination to TcO

. The human images of

99m

Tc-TRODAT-1 showed

localization at the basal ganglia, which correlates with the binding to the dopamine

transporters (DAT).

Imaging of dopamine

transporters

[37]

99m

Tc BMS 181321 Nitroimidazole-derivatized TcO

amine oxime complexes. Hypoxic tissues can be

differentiated from normal tissues on the basis of their redox proﬁle inside the cell. The

radiopharmaceutical should enter the cell and be reduced in a hypoxic environment.

Hypoxia targeting [38]

99m

Tc-sestamibi A monocationic hexakis-isonitrile (2-methoxy-2-methyl-1-propyl) isonitrile, where

techenetium is present with oxidation number+1. This is a very rare Tc oxidation state,

but the complex is very kinetically stable. The

99m

Tc-sestamibi is a myocardium

perfusion agent, but it was also demonstrated that the

99m

Tc-sestamibi is transported

out of tumor cells expressing MDR by the Pgp glycoprotein, allowing its use for MDR

evaluation.

Evaluation of

myocardium

perfusion; MDR

detection

[39,40]

99m

Tc-annexin V Annexin V labeled with

99m

Tc(CO)

(OH

)

. The annexin V is a protein that binds to the

phosphatidylserine residues present at the membrane of apoptotic cells. It was

demonstrated that the

99m

Tc labeling using the tricarbonile does not modify the cell

afﬁnity of annexin V.

Apoptosis tracer [41]

99m

Tc-P829 Radiopharmaceutical that binds to the somatostatin receptors overexpressed in a large

variety of tumors. The labeling using the precursor

99m

Tc(CO)

(OH

)

does not need

the presence of a reductor species, an advantage as it protects the disulﬁde peptide

bond that is essential to its receptor recognition.

Neuroendocrin tumor

detection

[42]

99m

Tc- RP419/DMP444 Peptide bearing the RGD (-Arg-Gly-Asp) sequence; it binds to the l GPIIb/IIIa receptors

expressed in the activated platelets, the ﬁrst step in the thrombus formation.

Thrombosis detection [43]

99m

Tc-ciproﬂoxacin The ciproﬂoxacin is an antibiotic. It is not known the coordination mechanism of the

technetium to this ligand and the radiolabeling yield is only ca. 40%.

Bacterial infection

diagnosis

[44]

Note: MDR, multidrug resistance.

114 Nuclear Medicine Physics

99m

Tc-sestamibi (

99m

Tc-hexakis-isonitrile) (Cardiolite) and

99m

Tc-tetrafosmin

([

99m

Tc-(1,2-bis((bis-ethoxyethyl)phosphino)ethane)]

) (Myoview) as myoc-

ardium perfusion agents. Pertechnetate itself (as eluted from the generator)

has diverse uses in NM, such as thyroid and parathyroid scintigraphy and

imaging of the salivary glands. Figure 4.11 shows the structures of some of

these technetium-99m complexes. As examples of

99m

Tc-bioconjugates (the

second group mentioned), we can include

99m

Tc-annexin V, for apoptosis

evaluation [38], the

99m

Tc-monoclonal antibody used in CEA-Scan [46], or

some peptide somatostatin analogs labeled with

99m

Tc [42].

R = CH

OCH

tetrofosmin

R = CH

C(CH

)

OCH

sestamibi

COOH

ECD

EtO

MAG3

HMPAO

–1

FIGURE 4.11

Chemical structure of some

99m

Tc radiopharmaceuticals:

99m

Tc-Sestamibi,

99m

Tc-tetrafosmin,

99m

Tc-L,L-ECD,

99m

Tc-D,L-HM-PAO, and

99m

Tc-MAG3.

Radiopharmaceuticals 115

4.8.2 Gallium and Indium: Radioisotopes and Their

Coordination Chemistry

There are three gallium radionuclides (

Ga,

Ga, and

Ga) and two indium

radionuclides (

111

In,

113

In) with suitable physical characteristics for use in

gamma scintigraphy or PET [30].

The isotope

Ga (t

1/2

= 78.1 h) is produced in a cyclotron by the nuclear

reaction

Zn(p,2n)

Ga starting with a

Zn-enriched sample. The

obtained is then separated either by solvent extraction or by an ionic exchange

process.

Ga, a positron emitter, is produced by a

Ge or

Ga generator and decays

by positron emission in 89% yield. The maximum energy of this positron is

1.899 keV, whereas the average energy per disintegration is 740 keV. The long

half-life of

Ge (t

1/2

= 280 days) makes it possible to obtain

Ga in situ,

without a cyclotron, although it is necessary to have an efﬁcient method of

separation of

Ga from

Ge.

Ga has a very convenient half-life of 68 min

compatible with the biokinetics and biological half-lives of a lot of low or

average molecular weight radiopharmaceuticals, such as peptides or oligonu-

cleotides [47], thus opening the possibility of developing lyophilized cold kit

formulations. The chemical properties of

Ge and

Ga are different enough

to permit an efﬁcient separation of the two radionuclides. In the literature,

two main strategies are found to isolate

Ga from

Ge:

1. Using organic matrices bearing phenolic groups that form very stable

complexes with Ge(IV) and which allow the elution of

GaCl

−

by using HCl as eluent. An alternative methodology uses

an N-methylglucamine-based polymer and a 0.1 M trisodium citrate

solution as eluent [48].

2. With inorganic oxides matrices, such as Al

, SnO

,Sb

, ZrO

and TiO

, eluted with HCl or EDTA [49]. Recently, a generator has

been introduced in the market where the

Ge or

Ga separation

is done on a TiO

column using a 0.1 M HCl solution as eluent

(Cyclotron Co, Obninsk, Russia). The reader is directed to excellent

reviews concerning this subject [50,51].

Ga is also a positron emitter (t

1/2

= 9.45 h) and is produced in a cyclotron

by the

Zn(p,2n)

Ga reaction. However, there are very few examples of

application of this radionuclide.

The radioisotope

111

In (t

1/2

= 67.2 h) is produced in a cyclotron, starting

from

111

Cd,

111

Cd(p,n)

111

In and decays by electron capture producing 173 keV

(89%) and 247 keV (95%) photons. The separation of the

111

In from the starting

material,

111

Cd, follows processes similar to those used to isolate

Ga.

113m

In (t

1/2

= 1.7 h) obtained with the generator

113

Sn/

113m

In emits γ radi-

ation with energy 393 keV. However, nowadays this radionuclide has been

replaced for most of its applications by

99m

Tc.

116 Nuclear Medicine Physics

The coordination chemistry of gallium and indium is of considerable great

interest, mostly due to the potential use of their radioisotopes in radio-

pharmacy [31,45,52]. Gallium and indium are metals belonging to the III B

group of the periodic table and under physiological conditions they only

exist in the +3 oxidation state. This fact is determinant for their radiochem-

istry. These two metals, together with boron and aluminum, are classiﬁed

as “hard acids” [53], and they prefer to form chemical bonds with ionic and

nonpolarizable Lewis bases such as nitrogen and oxygen atoms (carboxylate,

phosphonate, and amino groups). The coordination chemistries of gallium

(III) and iron (III) are very similar; and, as we will see, this fact is crucial in

the use and preparation of gallium radiopharmaceuticals. The coordination

chemistry of In (III), having a larger ionic radius, is comparable with that of

Y (III) and lanthanides.

In solution, the hydrated cations Ga (III) and In (III) are only enough stable

under acidic conditions, hydrolyzing at higher pH values and leading to the

insoluble hydroxides Ga(OH)

and In(OH)

M(H

O → M(OH)(H

; (4.8)

M(OH)(H

O → M(OH)

+(H

; (4.9)

M(OH)

+(H

→ M(OH)

(s) +H

+3H

O. (4.10)

As an example, in a gallium(III) solution containing 1 mCi/mL (which

corresponds to a

Ga concentration of 4 ×10

−10

M and to a

Ga concen-

tration of 2.5 ×10

−8

M), Ga(OH)

precipitation occurs for pH ≥ 3 if there are

no stabilizing ligands present in solution [54]. Even though it is possible to

use gallium-68 hydroxide-based colloids for liver–spleen PET imaging [55],

normally these hydrolysis reactions prevent the preparation of gallium radio-

pharmaceuticals. In contrast with what happens with In(OH)

, the hydroxide

Ga(OH)

is amphoteric; and in addition to being soluble in acids, it is soluble

and at basic pH through the reaction,

Ga(OH)

(s) +OH

−

→ Ga(OH)

−

, (4.11)

which allows the redissolution of Ga(OH)

For their use as radiopharmaceuticals, the compounds of gallium and

indium must be thermodynamically stable at physiological pH values and/or

kinetically inert on the timescale of the procedures used in NM.

4.8.2.1 Gallium and Indium Ligands

On the basis of their structural properties, one can establish two main classes

of ligands suitable for coordinating In

or Ga

: linear chain ligands and

macrocyclic ligands. In addition to the metal coordinating groups, many of

the ligands belonging to the two classes possess other functional groups

Radiopharmaceuticals 117

HOOC

NNN

COOH

Bz-NHCSNH-mAb

(a) (b)

COOH

CONH-mAb

FIGURE 4.12

Structures of the bifunctional chelators (a) SCN-BzDTPA (octadentate) and (b) cDTPA (hepta-

dentate) (Adapted from M. W. et al., Inorg. Chem., 25:2772–2781, 1986.). The arrow shows the

coupling site.

(e.g., –NH

or –COOH), which allow the functionalization with a macro-

molecule. DTPA (diethylenetriaminepentaacetate) is an example of a widely

used linear chain chelator in radiopharmacy, such asfor metal radiolabeling of

monoclonal antibodies [56] and peptides [57]. The amino acid conjugation is

normally achieved through the cyclical bis-anhydride derivative of the DTPA

(cDTPA) [58]. This method has the inconvenience of sacriﬁcing one of the car-

boxylate groups of the DTPA to form an amide bond with the lysine residue

of the lateral chain of the antibody such that only seven coordinate sites of

the DTPA stay available for coordination to the metal, thus lowering the ther-

modynamic stability of the chelate. For this reason, the use of another deriva-

tive of DTPA, l-(p-isothiocyanatobenzyl)-diethylenetriaminepentaacetate (p-

SCN-Bz-DTPA), has been proposed, where the linking group to the antibody

uses one carbon of the skeleton of the DTPA(Figure4.12) [59]. However,DTPA

only forms a complex that is sufﬁciently stable to permit its use in vivo with the

. Another linear chelator has, therefore, been proposed for studies with

gallium: the desferrioxamine-B (DFO) (Figure 4.13), which is used as a bifunc-

tional chelator with high yield for

67/68

labeling [60]. In addition, DFO

presents a –NH

group, which is available for conjugation with biomolecules,

such as peptides or antibodies.

(CH

)

(CH

)

(CH

)

(CH

)

(CH

)

(CH

)

COOH

OOH

FIGURE 4.13

Structure of the desferrioxamine-B (DFO), a bifunctional chelator coupled to biomolecules via

the −NH

group or a succinyl spacer (Adapted from P.M. Smith–Jones, et al., J. Nucl. Med., 35:

317–325, 1994.).