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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5624_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 12
99m
Tc
Radiopharmaceutical
Chemistry
Dionysia Papagiannopoulou
Department of Pharmaceutical Chemistry, School of Pharmacy,
Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
12.1 INTRODUCTION
Technetium-99m is a γ-emitting radionuclide (Eγ=141 keV, 89% abundance, t
with diagnostic applications in nuclear medicine for planar scintigraphy and single photon
emission computed tomography (SPECT ). Its nuclear properties are ideal for imaging
99
with γ cameras, it is produced from
availability, and its radiopharmaceuticals can be easily prepared in the radiopharmacy via
commercial kits. Today there exist numerous
nostic procedures (Table12.1), of which the
common (Figure12.1).
The development of new
disease-specic imaging agents. In this chapter, the bibliography has been surveyed from
2000 to the present, and the
the relevant sections. In these years, new
99m
new
Tc-complexes have been proposed as probes with superior properties over older
ones, and many research eorts have focused on the design of new targeted
pharmaceuticals based on the advances of chemical biology in the identication of suitable targeting vectors.
Handbook of Radiopharmaceuticals: Methodology and Applications, Second Edition.
Edited by Michael R. Kilbourn and Peter J.H. Scott.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
99m
Tc radiopharmaceuticals is driven by the need to obtain
99m
Tc-labelled imaging agents developed are summarized in
99m
Mo/
Tc generators with low cost and worldwide
99m
Tc radiopharmaceuticals for various diag-
99m
Tc perfusion imaging agents are the most
99m
Tc-labelling strategies have been developed,
=6 hours)
1/2
99m
Tc radio-
Table 12.1 Technetium-99m radiopharmaceuticals.
–
[
O
99m
Tc-Radiopharmaceutical Medical application
99m
Tc-Sestamibi Myocardial perfusion, breast cancer imaging, parathyroid
aging
99m
Tc-Tetrofosmin Myocardial perfusion
99m
Tc-Medronate (MDP)
99m
Tc-Oxidronate (HDP)
99m
Tc]Tc- H M PAO Brain perfusion
d,l-[
99m
l,l-[
Tc]Tc- ECD Brain perfusion
99m
[
Tc]Tc- M AG
99m
[
Tc]Tc- D MS A Tc(III)DMSA: kidney scan
99m
[
Tc]Tc-glucoheptate(GH) Renal imaging
99m
[
Tc]Tc- DTPA Renal imaging/(aerosol) Lung ventilation
99m
Tc-Etifenin/Mebrofenin/
3
im
Bone scintigraphy
Renal perfusion
Tc(V)DMSA:
medul
lary
th
Hepatobiliary scintigraphy
yroid
ca
rcinoma
im
aging
Disofenin
99m
Tc-colloids Liver/spleen scintigraphy, bone marrow imaging
99m
Tc-albumin macroaggregate Lung perfusion+
99m
[
Tc][Tc O4]
99m
Tc-Tilmanocept Lymphoscintigraphy
99m
Tc-Tektrot yd Imaging of tumors overexpressing somatostatin receptors
99m
Tc-Apcitide Deep venous thrombosis imaging
99m
Tc-Nofetumomab Merpen-
tan
99m
Tc-Arcitumomab Monoclonal antibody Fab΄ for colorectal cancer imaging
99m
Tc-Sulesomab
99m
Tc-Besilesomab
99m
Tc-red blood cells Radionuclide angiography, blood pool, GI bleeding, spleen
99m
Tc-white blood cells Infection imaging
−
Thyroid imaging, salivary glands, Meckel’s diverticulum
im
aging
(e
gas
.g.
tro-entero-pancreatic
neu
roendocrine
tu
mors)
Monoclonal antibody fragment Fab for small-cell lung can-
cer imaging
Monoclonal antibody Fab΄ for infection imaging
Monoclonal antibody for infection imaging
im
aging
(d
enaturated)
O
N N
Tc
NN
OHO
99m
Tc]Tc-D,L-HMPAO
EtOOC
N N
99m
[
Tc]Tc-L,L-ECD
COOEt
O
H
Tc
SS
Figure 12.1 Structures of common
–
O
O
O
N N
Tc
N
S
COOH
99m
[
Tc]Tc-MAG
99m
Tc-radiopharmaceuticals.
R
R
O
3
N
N
R= CH2C(CH3)2OCH
99m
R
N
C
C
N
C
Tc
C
N
C
N
R
Tc-Sestamibi
+
R
R
R
R
P P
P
R
R
R= -CH2CH2OCH2CH
99m
3
Tc-Tetrofosmin
+
R
R
O
Tc
P
O
R
R
3
R=
O
99m
O
R
N
O
O
O
O
Tc
N
R
O
O
H
N
Br
376 Handbook of Radiopharmaceuticals
99m CHEL ATORS
b. L = tricine + phosphine/pyridine
R
“2+1” mixed ligand
AND COMPLEXES
Various
chelator, lead to complexes with dierent physicochemical characteristics (Figure12.2).
99m
[
yield and are stable, especially with suitable tetradentate ligands. The N
that have been used the most for the preparation of [
are the bisaminethiols (BAT ) (also known as diaminedithiols, DADT), diamidedithiols
(DADS), and monoamino monoamido dithiols (MAMA). The respective complexes [
TcO-BAT and [
perfusion agents or for brain receptor imaging. The N
tion of [
similar cysteine-containing tripeptide or tetrapeptide chelators. These chelators may
be incorporated at the end of a peptide sequence for the development of
peptides[1]. The respective complexes [
and exhibit high renal excretion. [
agents. The “3+1” mixed-ligand [
coordination of a tridentate dithiolate (S,X,S) ligand (X=O, S or NR) and a monodentate
99m
Tc-labelling strategies have been developed that, depending upon the type of
Tc]Oxotechnetium(V) complexes are widely used because they are formed in high
chelators
99m
Tc]oxotechnetium(V) complexes
99m
Tc]TcO-MAMA are neutral and lipophilic and have been used as brain
S chelators used for the prepara-
99m
Tc]oxotechnetium(V) complexes are mercaptoacetyltriglycine (MAG3) and
99m
Tc]TcO- M AG3 and [
99m
Tc]Tc- MAG3 is one of the most used renal imaging
99m
Tc]oxotechnetium(V) complexes are formed by the
3
99m
Tc]TcO-DADT are anionic
2S2
99m
Tc-labelled
99m
Tc]
O
N N
99m
[
Tc]TcO-BAT
O
Tc
SS
R
O
N
N
Tc
SS
99m
[
Tc]TcO-MAMA
R
N
S
III
S
Tc
S
C
N
R
99m
[
Tc]Tc(NS3)(CNR)
“4+1” mixed ligand
NH
R
99m
[
Tc]Tc(CO)3(RS-cysteine)
OC
2
S
O
Tc
CO
CO
O
N
OC
99m
Tc][Tc(CO)3(DPA)]
[
O
O
OC
99m
[
Figure 12.2 Structures of
O
X
Tc
S
X=O,S,N(R)
99m
[
Tc]TcO(SXS)(SR’)
“3+1” mixed ligand
+
R
N
N
Tc
CO
CO
+
R
N
Tc
CO
–
O
O
CO
Tc][Tc(CO)3(IDA)]
99m
Tc-complexes.
S
R′
S
R
N
N
N
Tc
OC
CO
99m
[
Tc][Tc(CO)3(pzNN)]
99m
[
–
+
O
HN
NH
Tc
N
N
O
H
H
2
2
99m
Tc][TcO2-tetramine]
[
+
NH
2
CO
X=C: [
+
X=N: [
O
NH
O
N
N
Tc
OC
CO
CO
Tc]Tc(CO)3(pic)(im)
R
R
4
4
P
Tc
P
R
4
R
4
+
HN
X
N
OC
99m
Tc]Tc(CO)3(Histidine),
99m
Tc]Tc(CO)3(TzHis)
N
R
99m
[
Tc][TcN(PNP)(DTC)]
H2N
O
Tc
CO
OC
Tc
OC
CO
99m
[
Tc]Tc(CO)3(Cp)
99m
Tc]CpTT
or [
N
O
CO
+
S
N
S
3
R
1
R
2
+
HO
O
N
L
L
99m
[
Tc]Tc-HYNIC complexes
a. L = tricine
N
N
L
Tc
L
c. L = EDDA
R
O
N
N
O
Tc
OC
CO
CO
99m
[
Tc]Tc(CO)3(PAMA)
B
–
O
R
B
B
B
B
B
R
C
B
C
B
B
Tc
CO
OC
CO
Tc][Tc(CO)3(carborane)]
[
H
99m
–
Chapter 12:
99m
Tc Radiopharmaceutical Chemistry 377
thiolate. The complexes [
99m
Tc][TcO(S,X,S)(S)] are neutral and lipophilic and have been
used for the development of brain perfusion as well as for brain receptor-targeted
imaging agents. The propyleneaminoxime chelator forms neutral [
complexes. D,L-[
useful brain perfusion imaging agents. Cationic trans-[
99m
Tc]oxotechnetium-hexamethylpropyleneamineoxime is one of the most
99m
Tc]dioxotechnetium(V) complexes
99m
Tc]oxotechnetium(V)
have also been applied in radiopharmaceuticals. Tetradentate ligands used for their preparation are the tetramine chelators, either acyclic (e.g. 1,4,7,11-tetraaza-undecane) or cyclic
(e.g. cyclam), as well as the X
hydroxymethylphosphine moieties as the P-donor forms hydrophilic
99m
The [
Tc]nitridotechnetium(V) complexes have been synthesized in the past in
-type (X=N or S) chelators. The latter ligand with two terminal
2P2
99m
Tc-complexes[2].
combination with bidentate (S,S) chelators such as the dithiocarbamate, which forms
neutral symmetrical complexes, [
99m
Tc][Tc N(S, S)2]. A complex of this type, [
99m
Tc]TcN -
NOET, was developed as a myocardial imaging agent. Of interest are the more recently
developed asymmetrical complexes with an aminodiphosphane (P,N,P) ligand that forms
the metal fragment [
ious bidentate chelators L and leads to asymmetrical mixed-ligand [
0/+
L]
complexes, cationic or neutral depending on the nature of L. For the formation
of these complexes, cysteine acting as a (S,N)
dithiocarbamates or dithiols (S,S)
99m
The [
Tc]Tc-hydrazino complexes are formed by the coordination of the
99m
Tc][Tc N(P,N,P)]2+. This fragment can be combined with var-
99m
Tc][Tc N(P,N,P)
−
or (S,O)2− bidentate chelator, as well as
−
, can be used[3,4].
6-hydrazinonicotinic acid (HYNIC) ligand, which acts as a bifunctional chelating agent,
complexed with technetium via the hydrazide-N, aromatic-N atoms and conjugated to
biomolecules via the carboxylate moiety. For the formation of the hydrazine complexes,
additional co-ligands are required to complete the coordination sphere, such as tricine
alone, or in combination with N,N′-ethylenediamine-diacetic acid (EDDA), ternary phosphines (e.g. triphenylphosphine-3,3′,3″-trisulfonate, TPPTS), or aromatic amines (e.g.
nicotinic or isonicotinic acid). In the case of [
99m
Tc]Tc-HYNIC-EDDA complexes, tricine is
required in the labeling mixture for ligand exchange and probably is not present in the
nal complex formed. In the case of the ternary ligands, tricine remains coordinated in
the nal complex. The technetium-99m HYNIC complexes have not been fully characterized at the macroscopic level. Their composition [
been identied by
99g
Tc-carrier-added mass spectrometry studies of the labeling mix-
99m/99g
Tc][Tc(HYNIC)(co-ligand)] has
ture. In these mixtures, more than one product can be formed, of which the formulas
99m/99g
[
Tc][Tc(HYNIC)(tricine)
1or2
co-ligands tricine and EDDA, [
and TPTTS, and [
99m/99g
Tc][Tc(HYNIC)(tricine)(nicotinate)] with co-ligands tricine and nico-
] with co-ligand tricine, [
99m/99g
Tc][Tc(HYNIC)(tricine)(TPTTS)] with co-ligands tricine
99m/99g
Tc][Tc(HYNIC)(EDDA)
1or2
] with
tinate were identied[5–7]. Each of these complexes exhibits dierent pharmacokinetic
properties and biological stability. The [
99m
Tc]Tc-HYNIC-tricine complexes are formed in
high yield, but isomers are observed, and the biological stability is relatively low. The
99m
[
Tc]Tc-HYNIC-EDDA complexes are more stable and exhibit better homogeneity; however, heating is required to obtain high labelling yield. The use of ternary ligands along
with tricine improves both stability and homogeneity[5, 6]. Furthermore, if the peptide
sequence conjugated to HYNIC has an additional donor (such as histidine or glutamate),
378 Handbook of Radiopharmaceuticals
it has been proposed that it may also participate in the coordination sphere of the
99m
[
Tc]Tc-HYNIC complex formed[8].
Organometallic
the combination of the tripodal/tetradentate tris(2-mercaptoethyl)amine (NS
and an isocyanide to form the neutral [
99m
Tc(I)-complexes with isocyanide or carbon monoxide ligands have been extensively
99m
Tc(III)-complexes of the “4+1” mixed-ligand system are formed with
) chelator
99m
Tc][Tc(NS3)(CNR)] complex[9, 10]. Organometallic
3
applied in radiopharmaceutical design. These complexes are six-coordinate with high
stability and inertness due to the metal–carbon bond and full-shell coordination, respectively. The [
99m
Tc][TcI(MIBI)6]+ complex (
isocyanide, is used as a myocardial and tumor imaging agent. The [
99m
Tc-Sestamibi), where MIBI is 2-methoxy-isobutyl-
99m
Tc]TcI-tricarbonyl
labeling approach is one of the most widely explored in the past two decades. By this
approach, the “semi-aqua” precursor fac-[
of chelators. The tridentate ligands that are used for the preparation of [
99m
Tc][Tc(CO)3(H2O)3]+ is complexed with a variety
99m
Tc]Tc- tr i c ar-
bonyl complexes may combine N, O, S, and P donor atoms. The (N,N,N) chelators usually
contain at least one aromatic amine and form cationic [
99m
Tc][Tc(CO)3(N,N,N)]+ complexes
in high yields[11, 12]. Chelators of this type include dipicolylamine (DPA) as well as its
lysine-based analogues prepared by the single amino acid chelate (SAAC) strategy[13,
14], where the tridentate chelator is built via reductive amination on the ε-NH
group
2
of a lysine residue. The (N,N,O) chelators that have been used are histidine and picolyl-
amine acetic acid (PAMA), which form neutral [
99m
Tc][Tc(CO)3(N,N,O)] complexes[15, 16].
A histidine analogue that is equally potent is the triazole-histidine (TzHis) ligand, where
1,2,3-triazole takes the place of imidazole in His. The [
99m
Tc][Tc(CO)3(TzHis)] complexes are
prepared by a two-step procedure that does not require intermediate purication: (i) the
ligand is formed by “3+2” cycloaddition “click” of an azide with L-propargyl-glycine, and
(ii) the product (TzHis) is reacted with [
99m
Tc][Tc(CO)3(H2O)3]+ precursor[17, 18]. Another
type of tridentate ligand is (N,O,O) chelator iminodiacetic acid, which forms an anionic
99m
[
Tc(CO)3(N,O,O)]− complex with lower lipophilicity[15]. In an analogous way, cationic
99m
[
Tc][Tc(CO)3(N,S,N)]+ and neutral [
99m
Tc][Tc(CO)3(N,S,O)] with thioether-containing che-
lators, as well as phosphine-containing (P,N,P), (P,S,S), (P,O,O) chelators, form stable
99m
[
Tc]Tc-tricarbonyl complexes[19–22]. The “2+1” mixed-ligand [
99m
Tc][Tc(CO)3]+ complexes
are used as well and contain bidentate chelators such as 3-hydroxypyridone (O,O),
dithiocarbamate (S,S), bipyridine (N,N), bisphosphine (P,P), and 2-picolinic acid (N,O). As
monodentate ligands, phosphines (P), isocyanides (CNR), and aromatic amines have been
used[23–29]. For labelling antibodies or immunoreactive constructs such as single-chain
scFv fragments or abodies with [
99m
Tc][Tc(CO)3]+, a histidine tag added in the aminoacid
sequence has proven to be ecient for coordination with the metal through the imidazole moieties[30–32]. [
cyclopentadienyls and carboranes, have also been developed. The “piano stool” [
[Tc(CO)
(η5-Cp)] complexes ([
3
99m
Tc][Tc(CO)3]+ complexes of ligands with η5 hapticity, such as
99m
Tc]CpTT) are compact in size and considered bioisosters
99m
Tc]
to the phenyl ring. Their importance in radiopharmaceutical design is that they oer the
possibility to obtain bioactive technetium-99m complexes via the “integrated” approach.
99m
The [
[TcO
Tc]CpTT complexes are prepared by various methodologies: (i) from [
]− by reaction with a carbonyl source (e.g. Cr(CO)6 or Mn(CO)5Br) and a ferrocene
4
99m
Tc]
Chapter 12:
99m
Tc Radiopharmaceutical Chemistry 379
as the cyclopentadienyl source (double ligand transfer)[33]; (ii) by reaction of [
[
Tc]TcN(PNP5)(DBODC)]+: R=Et
RO
R
+
[Tc(CO)
99m
[
Tc][Tc(CO)3(H2O)3]+ with a cyclopentadiene-carbonyl derivative (e.g. ketone) or its dimer
]+ with a ferrocene (single ligand transfer)[34, 35]; and (iii) by reaction of
3(H2O)3
99m
Tc]
(e.g. Thiele’s acid)[36, 37]. These complexes are neutral and lipophilic and have been used
for the development of targeted radiopharmaceuticals. The isolobal to Cp
−
ligand nido-
carborane is prepared from dicarba-closododecaboranes followed by deprotonation, and
the anionic [
99m
Tc][Tc(CO)3C2B9H10]− complex is formed. Carboranes have a similar size to
the phenyl ring and demonstrate low toxicity[38].
12.3 MYOCARDIAL IMAGING AGENTS
Myocardial perfusion scintigraphy is one of the most frequently performed nuclear medicine procedures useful for the evaluation of the myocardial function. The lipophilic, cationic
99m
Tc radiopharmaceuticals that are mostly used for this procedure are
99m
Tc-Tetrofosmin. These agents do not exhibit ideal myocardial extraction and furthermore display prolonged hepatic clearance that, due to the proximity of the liver to the
heart, makes it dicult to assess the myocardial perfusion, especially in the lower areas
of the left ventricle. Therefore, it is highly desirable to develop new myocardial agents
with better organ distribution and faster hepatic clearance. More than two decades ago, a
novel myocardial imaging agent was developed–the neutral nitridotechnetium complex
99m
[
Tc][Tc N(NOET)2] (NOET is N-ethoxy,N-ethyl-dithiocarbamate)–that exhibits better
extraction properties compared to
tribution similar to
developed based on the [
201
Tl. In 2000, a new class of nitrido technetium(V) complexes was
99m
Tc][TcN(aminediphosphane, PNP)]2+ metal fragment that, in
99m
Tc-Sestamibi and
99m
Tc-Tetrofosmin as well as redis-
combination with dithiocarbamate (DTC) as co-ligand, forms asymmetrical and monocationic complexes of the type [
complexes [
99m
Tc][TcN(PNP3)(DBODC)]+ and [
99m
Tc][Tc N(PNP)(DTC )]+. From this series of compounds, the
99m
Tc][TcN(PNP5)(DBODC)]+, where DBODC
is bis-N-ethoxyethyl-dithiocarbamato, PNP3 is bis(dimethoxypropylphosphinoethyl)methoxyethylamine, and PNP5 is bis(dimethoxypropylphosphinoethyl)-ethoxyethylamine,
respectively (Figure12.3), exhibited superior properties as myocardial imaging agents. In
particular, high myocardial uptake of 3.65 ± 0.56 and 3.69 ± 0.29% ID/g was displayed by
99m
[
Tc][TcN(PNP3)(DBODC)]+ and [
99m
Tc][TcN(PNP5)(DBODC)]+ at 10 minutes p.i., respectively,
99m
Tc-Sestamibi and
O
O
O
+
N
P
S
Tc
P
N
99m
[
Tc][TcN(PNP3)(DBODC)]+: R=Me
99m
Figure 12.3 Structures of
N
S
O
O
O
O
99m
Tc-labelled myocardial imaging agents.
380 Handbook of Radiopharmaceuticals
O
O
N
P
Tc
P
N
O
99m
[
Tc][TcN(PNP5)(MPO)]
N
Tc
CO
R
N
R
N
N
R
CO
3
O
O
+
H
S
N
O
O
+
O
O
[
O
O
O
N
P
P
Tc
CO
OC
CO
99m
Tc][Tc(CO)3(15C5-PNP)]
O
O
+
N
R
R
N
R
R
+
R
OC
R=CH2OCH
99m
[
Tc]Tc-TMEOP
which was retained for a prolonged time, comparable to that of
99m
Tc-Sestamibi and
99m
Tc-
Tetrofosmin[39, 40]. Furthermore, fast lung and liver washout was observed, with heart-
to-lung and heart-to-liver ratios higher than those of
99m
Tc-Sestamibi and
at 60 minutes and 120 minutes p.i.. In preclinical evaluation, the heart-to-liver ratio of [
[TcN(PNP5)(DBODC)]
99m
Tc-Tetrofosmin with ratios of 2.6 ± 0.2 and 5.8 ± 0.7, respectively, at 60 minutes p.i.[41]. In
subcellular experiments, [
+
was found to be 18.4 ± 2.0, which was superior to
99m
Tc][TcN(PNP5)(DBODC)]+ behaved as a substrate of the multi-
99m
Tc-Tetrofo smin
99m
Tc-Sestamibi and
99m
Tc]
drug resistance-associated protein P-glycoprotein and also displayed selective mitochon-
drial accumulation[42]. Another tracer of the same type that contains a crown-ether moiety,
99m
[
Tc][TcN(N-(dithiocarbamato)-2-aminimethyl-15-crown-5)(N,N-bis[2–(bis(3-ethoxypropyl)-
+
phosphino)ethyl]methoxyethylamine)]
similar biodistribution properties to [
nitridotechnetium tracer [
99m
Tc][Tc N(PNP5)(MPO)]+, where MPO is 2-mercaptopyridine
99m
([
Tc]TcN-15C5), was developed and exhibited
99m
Tc][TcN(PNP5)(DBODC)]+[43, 44]. In addition, the
N-oxide (Figure12.3), was developed and displayed heart uptake of 2.62 ± 0.34% ID/g. Its
heart-to-liver ratio of 12.75 ± 3.34 at 30 minutes p.i. was higher than that of [
(DBODC)]
+
(MPO)]
and
+
(6.01 ± 1.45) and
99m
Tc-Sestamibi displayed almost identical subcellular distribution and localiza-
99m
Tc-Sestamibi (2.90 ± 0.22)[45]. In addition, [
99m
Tc][Tc N(PNP5)
99m
Tc][Tc N(PNP5)
tion mechanisms[46].
By a dierent approach, the cationic [
99m
Tc]technetium-tricarbonyl complexes
were developed as well for myocardial perfusion imaging. First, complexes of the
99m
type [
Tc][Tc(CO)3(CNR)3]+ with three isocyanide ligands were developed, which,
although they exhibited myocardial uptake, did not display superior biodistribution
properties[47, 48]. A series of [
99m
Tc][Tc(CO)3(PNP)]+-type complexes were developed
that exhibited high myocardial uptake, and among them, the crown-ether containing
ligand [
99m
Tc][Tc(CO)3(15C5-PNP)]+ (15C5-PNP: N-[15-crown-5)-2-yl]-N,N-bis[2-(bis(3ethoxypropyl)phosphino)ethyl]amine) (Figure12.3) exhibited approximately 2.5 times
better heart-to-liver ratio than that of
similar to [
PNP)]
99m
Tc][TcN(PNP5)(DBODC)]+[22]. In preclinical evaluation, [
+
displayed favorable in vivo kinetics[49]. Furthermore, cationic [
99m
Tc-Sestamibi at 30 minutes p.i. and properties
99m
Tc][Tc(CO)3(15C5-
99m
Tc]tris(pyrazolyl)
methane-technetium-tricarbonyl complexes were developed with a tripodal chelator that
oers multiple possibilities of functionalization. In particular, one of these complexes,
99m
[
Tc][Tc(CO)3{κ3-HC[3,4,5-(CH3OCH2)3pz]3}]+ ([
99m
Tc]Tc-TMEOP, Figure12.3), exhibited
high heart uptake and superior heart-to-liver ratio of 6.98 ± 1.66 compared to that of
99m
Tc-Sestamibi and
utes p.i.[50, 51]. The heart-to-liver ratio of [
99m
[
Tc][TcN(PNP5)(DBODC)]+ (6.01 ± 1.45 at 30 minutes p.i.) and [
(∼5) but inferior to that of [
99m
tion, [
Tc]Tc-TMEOP displayed a heart-uptake mechanism similar to that of the other
reported monocationic
99m
Tc-Tetrofosmin (2.48 ± 0.30 and 2.66 ± 0.40, respectively) at 40 min-
99m
Tc]Tc-TMEOP is comparable to that of
99m
Tc][Tc(CO)3(15C5-PNP)]+
99m
Tc][Tc N(PNP5)(MPO)]+ (12.75 ± 3.34). In preclinical evalua-
99m
Tc cardiac agents and is associated with its accumulation in the
mitochondria. Furthermore, cyclosporin A studies indicated that the fast liver and kidney
clearance kinetics was mediated by Pgp[52, 53]. Additional studies on the metabolism of
these ether tracers indicated that the position of the ether moieties on the pyrazole ring
is crucial for its ability to exhibit signicant myocardial uptake[54].
Chapter 12:
99m
Tc Radiopharmaceutical Chemistry 381
12.4
OC
[
Tc]CpTT-PA
O
OH
99m
Tc
Heart disease can result in regional alterations of the myocardial fatty acid metabolism.
Radiolabelled fatty acids (FA) such as 15-(p-[
acid, are useful in the diagnosis of heart disease. The development of
123
I]iodophenyl)-3(R,S)-methyl pentadecanoic
99m
Tc-FA for this
purpose is highly desirable due to the lower cost and wider availability of technetium-99m.
One eort was based on the [
99m
Tc]oxotechnetium “3+1” mixed-ligand complexes
of the type [SNS/S] and [SSS/S] bearing FA either on the monodentate thiol or on the
tridentate chelator. These tracers exhibited low in vivo myocardial uptake[55, 56]. Also,
a series of [
99m
Tc]TcO-MAMA-FA complexes with hexanoic, dodecanoic, and hexadeca-
noic acids were developed. The highest initial myocardial uptake in mice was observed
99m
for [
Tc]TcO-MAMA-hexadecanoic acid (Figure12.4) (11.22 ± 0.25% ID/g at 0.5 minutes
and 2.40 ± 0.22% ID/g at 5 minutes p.i., respectively), which exhibited the highest heartto-blood ratio of 3.6 at 2 minutes p.i.. Furthermore, this tracer was able to undergo in
vivo metabolism, since its metabolite [
the urine[57]. In another approach, asymmetrical cationic, or neutral [
99m
Tc]TcO-MAMA-butanoic acid was detected in
99m
Tc][Tc N(PNP)
(L-FA)], complexes were developed, where L was 2,3-dimercaptopropanoic acid or
dithiocarbamate linked to undecanoic and dodecanoic acids[58]. The
99m
Tc-tracers
exhibited fast liver and lung washout, and the highest heart uptake was observed for
the cationic dithiocarbamate tracer conjugated to dodecanoic acid, [
(DTC11)]
+
(Figure12.4), with values of 1.07 ± 0.02 and 0.59 ± 0.03 %ID/g at 5 and 60 min-
99m
Tc][Tc N(PNP3)
utes p.i., respectively. However, more detailed heart-extraction experiments showed
O
N NH
Tc
SS
99m
[
Tc]TcO-MAMA-HDA
S
S
Figure 12.4 Structures of
III
C
CO
N
99m
Tc]Tc(NS3)(CN-C11S)
[
99m
S
99m
Tc-labelled fatty acids.
N
Tc
S
Tc
CO
382 Handbook of Radiopharmaceuticals
O
O
Tc
CO
N
CO
O
N
P
Tc
P
O
99m
[
Tc][TcN(PNP3)(DTC11)]
O
99m
[
+
H
S
N
S
O
Tc]CpTT-15-oxo-PTA
O
+
O
S
OH
O
OH
O
O
OH
O
OH
OC
that the biodistribution prole was similar to that of the heart agents
99m
and [
addition, similar [
teine was coordinated either as [S,N]
Tc][TcN(PNP)(DBODC)]+, while its hepatic metabolism pattern was complex. In
99m
Tc][TcN(PNP)(cysteinyl-FA)] complexes were developed where cys-
−1
or as [S,O]2− bidentate ligand leading to either
99m
Tc-Sestamibi
cationic or neutral complexes, respectively[59, 60]. The cationic tracer exhibited
myocardial uptake of 9.88 ± 2.99% ID/g and 1.39 ± 0.36% ID/g at 2 and 30 minutes p.i.,
respectively.
A series of “4+1” mixed-ligand
99m
Tc-complexes were developed with tris(2-mercaptoethyl)amine as the tetradentate ligand and isocyanide monodentate ligands of varying
length FAs. Inserted in some of these FA monodentate ligands was either a sulfur heteroatom or a phenylene group to block/slow the β-oxidation. High myocardial extraction rates up to 26% injected dose (ID) were observed for these tracers in an isolated
Langendor rat heart model. In vivo, the tracers exhibited fast metabolism at 60 minutes
p.i., although no myocardial metabolism was observed. The highest heart uptake was 2%
ID/g, and the heart-to-blood ratio was 8.6 ± 0.1 at 5 minutes p.i. for the derivative with
the isonitrile ligand 5-[6-(isocyanohexyl)thio]pentanoic acid, [
99m
Tc]Tc(NS3)(CN-C11S)
(Figure12.4)[61, 62]. Furthermore, “4+1” mixed-ligand technetium-99m complexes were
developed where the
99m
Tc-chelate was placed in a central position of the compound
for improved myocardial prole following the sequence: carboxylic group, alkyl chain,
99m
Tc-chelate, and lipophilic tail. The myocardial rst-pass extraction of the compounds
was up to 20% of the injected dose (% ID) in the perfused heart, and the tracers exhibited fast liver clearance[63]. Some of these tracers were evaluated in isolated perfused
rat heart models, where it was found that the myocardial extraction was between 15.2%
and 33.0%. Further studies in knockout H-FABP
−/−
and H-FABP
+/+
mice, where H-FABP is an
intracellular protein that binds and transports FA, showed that H-FABP plays an important role in the myocardial uptake and retention of these “4+1”
99m
Tc-FA tracers[64].
Metabolism studies showed that the tracers did not undergo mitochondrial metabolism[65].
99m
The [
99m
of
cyclopentadienyl (CpTT) pentadecanoic acid, [
Tc]technetium-tricarbonyl approach was also used for the development
Tc-labelled FAs[66–69]. From these tracers, the [
99m
99m
Tc]technetium-tricarbonyl-
Tc]CpTT-PA (Figure12.4), exhibited high
myocardial uptake and retention with values of 3.85 ± 0.58 and 1.27 ± 0.28% ID/g at 1 and
30 minutes p.i., respectively, and maximum heart-to-blood ratio of 4.60 at 10 minutes
p.i.. In comparison, 15-(p-[
123
I]-iodophenyl)pentadecanoic acid exhibited heart uptake
of 7.59 ± 1.00 and 4.19 ± 1.66% ID/g at 1 and 30 minutes p.i., respectively, and maximum
heart-to-blood ratio of 12.46 at 2 minutes p.i.. The tracer [
cardial β-oxidation metabolism down to the [
99m
Tc]CpTT-propionic acid metabolite,
99m
Tc]CpTT-PA exhibited myo-
as Langendor perfusion study exhibited, where approximately 34% of the perfused
99m
[
Tc]CpTT-PA was retained in the heart, and approximately 33% of the perfusate was
present as the metabolite[67]. In another study, the tracer [
99m
Tc]CpTT-16- oxo-HDA,
where HDA is hexadecanoic acid, was developed and exhibited myocardial uptake and
retention with values of 9.03 ± 0.17 and 2.16 ± 0.19% ID/g at 1 and 30 minutes p.i., respectively, and maximum heart-to-blood ratio of 3.76 at 30 minutes p.i.. This tracer also
Chapter 12:
99m
Tc Radiopharmaceutical Chemistry 383
exhibited myocardial metabolism down to the [
99m
Tc]CpTT-4-oxo-butyric acid metabolite[68]. To create steric hindrance in FA metabolism and enhance the myocardial retention of the radioactivity, the thiophene moiety was introduced in the β-position of the
fatty acid chain in 15-[cyclopentadienyl-technetium-tricarbonyl]-15-oxo-pentadecanoyl
thiopheneacetic acid ([
99m
Tc]CpTT-15-oxo-PTA, Figure12.4). This tracer showed myocardial uptake of 9.39 ± 1.10 and 1.48 ± 0.14% ID/g at 1 and 30 minutes p.i., respectively, with
a maximum heart-to-blood ratio of 5.7 at 15 minutes p.i., while no heart metabolism was
detected[69]. More recent modications in [
99m
Tc]CpTT-FA complexes did not result in a
signicant improvement[70, 71].
12.5 BRAIN IMAGING AGENTS
12.5.1 5-HT1A Imaging Agents
The imaging of 5-HT1A receptors may be useful in the assessment of neuropsychiatric
and neurodegenerative disorders. For this purpose, the pharmacophore moiety ortho-
methoxyphenyl-piperazine (oMPP) of the true 5-HT
conjugated to various neutral and lipophilic technetium complexes with the ability
to cross the blood-brain barrier. In one eort, the [
were developed where the N
via a 6-carbon alkyl chain (Figure12.5). The
for the 5-HT
3
[
H]8-OH-DPAT, as well as good selectivity versus 5-HT2A (IC50 of 922 nM against [3H]
ketanserin). The
receptor with IC50 value of 1.29 nM against the selective 5-HT1A agonist
1A
99m
Tc-tracer exhibited initial brain uptake of 0.56 ± 0.07% ID at 2.5 min-
chelator was conjugated to 2-(1-piperazino)phenol
2S2
99g
Tc-complex displayed a high anity
utes p.i., while in vitro autoradiography indicated its accumulation in 5-HT
rich brain regions[72]. The “4+1” concept was used as well for the development of
M(NS
)(CN-C4/5/6-o MPP) (M=Re or
3
99m
Tc) complexes where oMPP was conjugated to
the isonitrile co-ligand via butyl (C4), pentyl (C5), and hexyl (C6) linkers (Figure12.5).
The Re-complexes exhibited a high anity for 5-HT
0.62 ± 0.17 and 4.5 ± 0.1 nM, respectively. Biodistribution studies in rats of the
complexes showed brain-uptake values between 0.3 and 0.5% ID/organ (5 minutes p.i.),
while in autoradiography, specic accumulation in 5-HT
was displayed[73]. Furthermore, a series of technetium and rhenium “3+1” complexes
were developed, where oMPP was conjugated either to the tridentate chelator or
to the monothiol[74–77]. The complexes [ReO(S
thiophenol (TP) or 4-methoxythiophenol (MeOTP) as co-ligands, where oMPP was
conjugated to the tridentate SNS ligand via a propyl (C3) linker, exhibited the highest
anity for 5-HT
with IC50 values of approximately 6 nM against [3H]8-OH-DPAT[75,
1A
76]. In the complexes where oMPP was conjugated to the monothiol, the analogous
complexes MO(S
lar anities for 5-HT
NMe)(S-C6-oMPP) (M=Re or 99Tc) (Figure12.5) exhibited subnanomo-
2
with IC50 values of 0.24 ± 0.08 and 0.13 ± 0.01 nM for Re and 99Tc
1A
complexes, respectively, as well as good selectivity versus 5-HT
antagonist WAY-100635 was
1A
99g/99m
Tc]TcO- DADT comp lexes
receptor-
1A
with IC50 values of 0.29 ± 0.01,
1A
receptor-rich brain regions
1A
N(C3-oMPP)(TP or MeOTP)] with
2
[74]. Furthermore,
2A
99m
Tc-
384 Handbook of Radiopharmaceuticals