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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5624_Библиотеки_им_академика_М_И_Перельмана.pdf
a dierent “3+1” complex of the type ReO(PNS)(S-X-oMPP) was developed, where
(P,N,S) is a phosphine-amide-thiol tridentate chelator and oMPP was conjugated to
the monothiol (S) with spacers of various lengths, X. The complex with the propyl
spacer X exhibited a high anity for 5-HT
selectivity versus 5-HT
. Biodistribution of the analogous
2A
brain uptake[78]. Furthermore, neutral complexes of the type MN(PS)(DTC) (M=
99m
Tc) were developed, of which the [99Tc]TcN(PSiso)(DTC-oMPP) complex, where
with IC50 of 2.35 ± 0.02 nM as well as high
1A
99m
Tc-tracer exhibited poor
99
Tc,
PSiso was diisopropyl-phosphinoethanethiol and DTC-oMPP was a dithiocarbamate
ligand conjugated to oMPP via a butyl spacer (Figure12.5), exhibited the highest
anity for 5-HT
(IC
=570 ± 30 nM against [3H]ketanserin). The
50
uptake, though[79]. The M(CO)
receptors with IC50 of 1.5 ± 0.1 nM and good selectivity versus 5-HT2A
1A
+
(M=Re,
3
99m
Tc-tracers exhibited negligible brain
99m
Tc) approach was also used[80, 81], and
from these tracers, the ones synthesized from the poly(mercaptoimidazolyl)borate
scorpionate (DMIB) chelator are of interest. The ligand was conjugated to either one
or two o MPP moieties, and the respective rhenium-tricarbonyl complexes exhibited
subnanomolar anities for 5-HT
with IC50 values of 0.172 ± 0.003 for the Re-complex
1A
conjugated to two o MPP moieties (Figure12.5) and 0.71 ± 0.02 nM for the Re-complex
conjugated to one oMPP moiety with moderate to good selectivity versus 5-HT
99m
The
Tc-tracer analogues exhibited an initial brain uptake of 1.38 ± 0.46% ID/g for
99m
the
Tc-complex conjugated to two oMPP moieties and 0.43 ± 0.12% ID/g for the
99m
Tc-complex conjugated to one o MPP moiety at 5 minutes p.i., with fast washout[82].
High brain uptake and specic retention in 5-HT
observed for a [
99m
Tc]technetium-tricarbonyl-cyclopentadienyl complex conjugated to
receptor-rich brain regions was also
1A
.
2A
oMPP (Figure12.5), where the brain uptake was 2.47 ± 0.04% ID/g at 5 minutes p.i.; furthermore, the hippocampus-to-cerebellum ratio in the brain was found to be 4.83, and
the cortex-to-cerebellum ratio was 2.77[83].
NN
O
N N
Tc
SS
99m
[
Tc]TcO-DADT-oMPP
N
[
P
S
99m
S
Tc
S
Tc]TcN-(SPiso)-DTC-Cn-oMPP), n=2-4
N
H
NN
n
Figure 12.5 Structures of
O
O
N
S
Tc
S
S
99m
[
Tc]TcO(S2NMe)(S-C6-oMPP)
O
99m
Tc-labelled 5-HT1A receptor imaging agents.
O
NN
O
N
4
99m
[
N
N
S
OC
Tc]Tc(CO)3(DMIB-bis-oMPP)
Chapter 12:
O
NN
H
B
N
H
N
S
Tc
CO
CO
99m
Tc Radiopharmaceutical Chemistry 385
O
N
S
S
III
C
N
Tc
S
99m
Tc]Tc(NS3)(CN-Cn-oMPP), n=4,5,6
[
O
NN
4
N
OC
NN
n
O
N
Tc
CO
CO
99m
[
Tc]CpTT-oMPP
O
O
N
12.5.2 Beta-Amyloid Imaging Agents
Imaging agents for β-amyloid plaques have proven to be useful in the diagnosis of
patients with cognitive impairment suspected for Alzheimer’s disease (AD). An ideal
amyloid imaging agent should be able to cross the blood-brain barrier and bind with a
high anity to the β-amyloid, while the unbound radioactivity washes out quickly. The
β-amyloid binding moieties that have mostly been explored are based on Thioavin
T and Chrysamine G dyes. Most of the eorts have used phenyl-benzothiazole as the
pharmacophore unit, but modications with benzofuran, benzoxazole, aurone, and avone moieties were also made. A number of aryl-benzothiazole (BTA ) derivatives were
conjugated to the BAT or MAMA chelators, and their respective rhenium and technetium
complexes were developed[84]. In a few studies, the suitable position of the BTA system
for conjugation to the metal chelator was investigated[85, 86]. Promising results were
obtained when the derivative 6-hydroxy-2-(4′-aminophenyl)-1,3-benzothiazole (6-BTA)
was conjugated to the MAMA chelator via the 6-hydroxyl position and a 5-carbon spacer.
The respective uorescent Re-MAMA-6-BTA complex selectively bound to the β-amyloid
aggregates in the brain sections of both transgenic mouse and AD patients. The analo-
99m
gous [
uptake (1.34 ± 0.16% ID/g at 2 minutes p.i.) but with low blood clearance (4.43% ID/g at
60 minutes p.i.)[87]. More recently, the BAT chelator was conjugated to 2-aryl-6-hydroxybenzothiazole pharmacophore moieties via the hydroxyl position-6 of benzothiazole
with various spacers ranging from propyl (C3) up to hexyl (C6) as well as with the ethyleneoxy spacer[88, 89]. From these complexes, it was shown that the M-BAT-6-PhBTA
complex (M=Re,
pharmacophore was used with a butyl spacer (Figure12.6) exhibited the most promising in vitro and in vivo behavior, with binding anity against [
plex)=8.8 ± 1.8 nM, and the highest in vivo brain uptake of the
ID/g at 2 minutes p.i.. The signicant brain uptake of this tracer was conrmed with in vivo
SPECT/CT imaging of rhesus monkeys[89].
developed[90, 91]. In one attempt, the cyclopentadienyl ligand was conjugated via
an amide bond with the 6-hydroxyl-derivatized 2-(4′-aminophenyl)-6-hydroxy-benzothiazole with propyl and pentyl spacers. The Re(CO)
moderate binding anities to β-amyloid and, in addition, they were able to bind in vitro
to β-amyloid in postmortem brain slices of transgenic mice and AD patients, although
99m
[
derivatives were prepared by amide linkage of cyclopentadienyl to the 2-aryl-6-hydroxybenzothiazole moiety. The rhenium complexes displayed a high anity for β-amyloid in
vitro (the highest anity was K
deposits on brain sections of transgenic mice and AD patients. The
were prepared by double-ligand transfer reaction from the respective ferrocene precursor and were found to bind to β-amyloid deposits in blood vessels of the brain section
of AD patients, while the highest initial brain uptake in normal mice was 1.06% ID/g at
Tc]Tc-MAMA-6-BTA complex could cross the healthy mouse brain with high initial
99m
Tc) where the 2-(N-4′-methylaminophenyl)-6-hydroxy-benzothiazole
125
I]IMPY of Ki (Re-com-
99m
Tc-tracer of 2.11 ± 0.11%
Furthermore, various [
99m
Tc][Tc(CO)3]+-labelled benzothiazole derivatives were also
(cp-BTA) complexes exhibited
3
Tc][Tc(CO)3(cp-BTA)] (Figure12.6) exhibited poor brain uptake <0.5% ID/g[92]. Similar
=12.39 ± 5.14), and they could intensely stain β-amyloid
i
99m
Tc-radiotracers
386 Handbook of Radiopharmaceuticals
2 minutes p.i.. Comparatively, the brain uptake between the amide and the ester derivatives was not signicantly dierent[93].
In the direction of
99m
Tc-labelled benzofuran (BF) derivatives, 5-hydroxyl-2(4′-
dimethylaminophenyl)-benzofuran was conjugated to the BAT and MAMA chelators via
a propyl chain at position-5. The Re-BAT-5-BF and Re-MAMA-5-BF complexes prepared
displayed binding anity to β-amyloid with K
respectively. The analogous [
99m
Tc]Tc-BAT-5-BF (Figure12.6) and [
values of 11.5 ± 0.56 and 24.4 ± 0.77 nM,
i
99m
Tc]Tc- MAMA-5-BF
were able to bind to β-amyloid plaques of transgenic mice in autoradiography brain tissue
sections and exhibited initial brain uptake of 1.34 ± 0.12 and 0.74 ± 0.15% ID/g, respectively, at 2 minutes p.i.. In addition, [
99m
Tc]Tc-BAT-5-BF exhibited maximum brain uptake of
1.37 ± 0.18% ID/g and fast washout, with blood percentage activity of 1.96 ± 0.06% ID/g, at
10 minutes p.i.[94].
In the development of
99m
Tc-benzoxazole (BOx ) derivatives, 2-(N,N-dimethyl-4′-
aminophenyl)-5-hydroxyl-benzoxazole was conjugated to the BAT and MAMA chelators
via a pentyl spacer at position-5 of benzoxazole (5-BOx). The Re-BAT-C5-5-BOx and
Re-MAMA-C5-5-BOx complexes exhibited in vitro binding anity to β-amyloid with K
values of 11.1 and 14.3 nM, respectively, against [
125
I]IMPY. In addition, the Re complexes
i
stained the β-amyloid plaques on the sections of transgenic mice. Biodistribution experiments in normal mice revealed that [
99m
Tc]Tc-BAT-C5-5-BOx displayed moderate initial
brain uptake (0.81% ID/g at 2 minutes), which quickly washed out from the brain (0.25%
ID/g at 60 minutes)[95]. From a series of BOx derivatives, Re-BAT-C3-5-BOx where 2-(N,Ndimethyl-4′-aminophenyl)-5-hydroxy-benzoxazole was conjugated to the BAT chelator at
position-5 via a propyl linker exhibited β-amyloid binding anity of K
against [
125
I]IMPY. Its analogous
99m
Tc-tracer ([
99m
Tc]Tc-BAT-C3-5-BOx, Figure12.6) exhib-
=15.86 ± 4.64 nM
i
ited the highest brain uptake of 1.55 ± 0.51% ID/g at 2 minutes p.i.[96]. Derivatives of the
quinoxaline type were also developed from the 2-(4′-aminophenyl)-6-hydroxy-quinoxaline scaold that was conjugated via a propyl chain to the BAT chelator and where the
4′-aminophenyl moiety was either N,N-dimethylated (BAT-C3-PQ-1), N-methylated (BATC3-PQ-2), or unmethylated (BAT-C3-PQ-3). The binding anity of [
99m
Tc]Tc- BAT-C 3 - PQ-1
in β-amyloid aggregates was higher compared to the other two derivatives, and its biodistribution study revealed moderate initial brain uptake of 0.88 ± 0.08% ID/g with reasonable clearance from the brain[97].
In another approach,
99m
Tc-labelled chalcone (Ch) derivatives were developed based
on the scaold 4-N,N-dimethylamino- 4′-hydroxy-chalcone, which was conjugated to
the chelators BAT and MAMA via propyl (C3) and pentyl (C5) spacers at the 4′-hydroxyl
position. All the
higher binding was obtained for the two C5 analogues [
Biodistribution in normal mice showed that the [
99m
Tc complexes exhibited binding to β-amyloid aggregates in vitro, and
99m
Tc]Tc- BAT/M AMA-C5- 4′-Ch.
99m
Tc]Tc- BAT-C 3 - 4′-Ch tracer (Figure12.6)
displayed the highest initial brain uptake (1.48% ID/g) at 2 minutes p.i. and fast brain
washout (0.17% ID/g at 60 minutes)[98]. Furthermore, similar avone and aurone
complexes were developed, where the 6-hydroxy-4′-N,N-dimethylamino-avone (FL) and
the analogous aurone (AR) were conjugated to BAT via a propyl spacer at the 6-hydroxyl
position. Both
99m
Tc-labelled derivatives showed specic binding in β-amyloid aggregates,
Chapter 12:
99m
Tc Radiopharmaceutical Chemistry 387
with the aurone exhibiting a higher binding anity compared to the avone (but lower
compared to the previously mentioned chalcone one) as well as similar in vivo characteristics in biodistribution studies. [
99m
Tc]Tc-BAT-FL and [
99m
Tc]Tc-BAT-AR (Figure12.6) exhibited low initial brain uptake of 0.64 and 0.79 %ID/g at 2 minutes p.i., respectively, and
fast elimination[99]. A [
anity (of the respective Re complex) of K
99m
Tc]Tc(CO)3-avonol derivate was also described with a binding
=11.16 nM in β-amyloid aggregates, with low
D
in vivo brain uptake (0.48 ± 0.05% ID/g at 5 minutes p.i.)[100].
In an integrated approach, chalcone-mimics were developed by replacing the chal-
cone aromatic ring by the [
99m
Tc]cyclopentadienyl-technetium-tricarbonyl moiety and
by inserting extended conjugated π systems (ethenyl, dienyl, and trienyl) (Figure12.6).
Low binding anities for β-amyloid were displayed with the highest that of the trienyl
derivative with K
=108 ± 16 nM, against [
i
125
I]IMPY. Apparently, as shown from the crystal
structure of these complexes, the metal-carbonyl core distorts the planarity of the
system, which decreases their anity. In terms of their brain uptake in normal mice, the
ethenyl-, dienyl-, and trienyl-chalcone mimics exhibited high brain uptake of 4.10 ± 0.38,
2.30 ± 0.27, and 1.11 ± 0.34% ID/g at 2 minutes p.i.[101].
A dierent pharmacophore, curcumin, was coordinated with [
99m
Tc][Tc(CO)3]+ in a
bidentate (O,O) fashion with co-ligands imidazole and cyclohexylisocyanide (Figure12.6).
The analogous rhenium complexes were able to stain postmortem brain section of AD
patients[102]. Furthermore,
99m
Tc-labelled dibenzylideneacetone (DBAc) derivatives were
developed, where the dibenylideneacetone scaold was conjugated to BAT and MAMA
chelators via propyl (C3) and pentyl (C5) chains. All the Re derivatives exhibited specic
β-amyloid binding, and the highest measured binding anity was K
by the Re-BAT-C5-DBAc complex. All the
99m
Tc tracers exhibited low brain uptake <0.5%
=13.6 nM displayed
i
ID/g[103].
The stilbene moiety has also been used for the design of
99m
Tc-probes. 3-Styrylpyridine derivatized with an oligoethyleneoxy linker was conjugated to the BAT chelator.
The Re complex with the bisethyleneoxy linker exhibited a higher binding anity with
K
=13.4 ± 3.3 nM against [
i
125
I]IMPY. The analogous
99m
Tc tracer (Figure12.6) exhibited brain uptake of 2.10 ± 0.22% ID/g at 2 minutes p.i.. In vivo SPECT/CT imaging in six
rhesus monkeys displayed an improvement in the brain uptake (1.94–2.63% ID within
20 minutes)[88].
12.6 RENAL IMAGING AGENTS
The most used renal imaging agent in nuclear medicine is [
approximately 50–60% of the renal excretion of the gold standard ortho -[
purate ([
burden. In an eort to develop new renal tracers with improved properties, a series of
99m
[
boxylate group that favors renal tubular transport, and the tracers were compared to
131
[
mixture of meso-LAN, DD - and LL-LAN isomers) to form [
388 Handbook of Radiopharmaceuticals
131
I]OIH), not currently used due to its suboptimal γ properties and β-radiation
Tc]technetium-tricarbonyl complexes were prepared with at least one dangling car-
I]OIH (Figure12.7). The rst eort described the labeling of lanthionine (LAN) (a
99m
Tc]Tc- MAG3, which exhibits
131
I]iodohip-
99m
Tc][Tc(CO)3(LAN)]− where
N
[
Tc]Tc-BAT-3-styrylpyridine
O
–
N N
Tc
O
3
SS
99m
[
Tc]Tc-BAT-6-PhBTA
Tc
O
X
O
5
CO
CO
99m
[
Tc]Tc(CO)3(cp-BTA), X=O, NH
S
S
N
NH
OC
N
O
N N
Tc
O
SS
99m
[
Tc]Tc-BAT-5-BF
O
N
O
O
N N
O
N
Tc
SS
99m
[
Tc]Tc-BAT-C3-5-BOx, X=C or N
O
N N
O
Tc
SS
99m
[
Tc]Tc-BAT-AR
Figure 12.6 Structures of
–
OOC
H2N
OC
99m
[
Tc][Tc(CO)3(LAN)]
Tc
S
CO
NH
CO
COO
2
–
–
–
[
Figure 12.7 Structures of
N
X
O
N
N
Tc
1 or 3
O
SS
99m
[
Tc]Tc-BAT-C3/C5-4′-Ch
O
N
O
O
N N
Tc
OC
CO
99m
[
Tc]CpTT-chalcone mimic, n=1–3
O
Tc
O
CO
n
2
N
SS
99m
99m
Tc-labelled β-amyloid imaging agents.
–
COO
2–
O
O
OC
99m
Tc][Tc(CO)3(NTA)]
99m
Tc-labelled renal imaging agents.
N
Tc
CO
O
CO
O
O
O
OC
99m
2–
[
Tc][Tc(CO)3(CMSA)]
S
Tc
CO
COO
O
CO
N
O
N N
O
Tc
SS
O
99m
[
Tc]Tc-BAT-FL
O
HO
O
O
O
OH
N
N
O
O
X
Tc
CO
OC
CO
N
99m
[
Tc]Tc(CO)3(curcumin),
X= water, imidazole, cyclohexylisocyanide
–
N
Tc
CO
COO
2–
O
O
CO
2
–
–
OOC
2–
O
O
O
OC
99m
2–
[
Tc][Tc(CO)3(TDSA)]
S
Tc
CO
O
CO
COO
O
–
3–
O
O
OC
3–
99m
[
Tc][Tc(CO)3(ASMA)]
LAN coordinates via the (N,S,N) donor atoms, while the two dangling carboxylates
lead to an overall anionic charge. The diasteromers were separated, and the two preparations of [
99m
Tc][Tc(CO)3(meso-L AN)]− and [
rats, where their excretion in urine was on average 88% that of [
was injected with both the
99m
Tc-tracer and [
99m
Tc][Tc(CO)3(DD,LL-LAN)]− were tested in
131
I]OIH (each animal
131
I]OIH) at 60 minutes p.i.. In humans, both
agents provided excellent renal images, with the plasma clearance averaging 228 ml min
99m
for [
Tc][Tc(CO)3(meso-L AN)]− and 176 ml min−1 for [
99m
Tc][Tc(CO)3(DD,LL-LAN)]−. At
three hours, both tracers showed good renal excretion, averaging 85% and 77% that of
99m
Tc Radiopharmaceutical Chemistry 389
Chapter 12:
−1
131
[
I]OIH, respectively[104, 105]. Two other [
prepared from the ligands carboxymethylmercaptosuccinic acid (CMSAH
cinic acid (TDSAH
), of which both [
4
99m
99m
Tc]technetium-tricarbonyl complexes were
Tc][Tc(CO)3(CMSA)]−2 and [
) and thiodisuc-
99m
3
Tc][Tc(CO)3(TDSA)]−3
are monoanionic with respect to the inner coordination sphere and have additional neg-
ative charges due to the dangling carboxylates: one in CMSA and two in TDSA, respectively. Renal excretion in rats was found to be 68 ± 1% for [
98 ± 1% for [
99m
[
Tc]Tc-tricarbonyl-nitrilotriacetic acid, [
99m
Tc][Tc(CO)3(CMSA)]−2 as a percentage of [
99m
Tc][Tc(CO)3(NTA)]−2, was also prepared, which
99m
Tc][Tc(CO)3(TDSA)]−3 and
131
I]OIH at 60 minutes p.i.[106].
has the advantage of being one single species (without isomers). This tracer was evaluated in normal rats, and the urinary excretion was 108 ± 9% and 101 ± 5%, respectively,
that of [
131
I]OIH at 10 and 60 minutes p.i.[107]. In healthy humans, [
exhibited comparable plasma clearance (475 ± 105 ml min
dose in the urine (91 ± 4%) with [
131
I]OIH (respective values were 472 ± 108 ml min−1 and
−1
) and percentage of injected
99m
Tc][Tc(CO)3(NTA)]−2
91 ± 6%) at three hours p.i.[108]. In patients with chronic kidney disease, the clearance
99m
of [
Tc][Tc(CO)3(NTA)]−2 and [
131
I]OIH were 177 ± 63 and 171 ± 66 ml min−1/1.7 3 m2 and the
percentage of injected dose in the urine was 77 ± 9% and 78 ± 11% at three hours p.i.,
respectively, indicating the similarity of the two agents[109]. Another tracer developed
was [
99m
Tc] technetium-tricarbonyl-aspartic-N-monoacetic acid, [
99m
Tc][Tc(CO)3(ASMA)]−2,
prepared both as a racemate as well as separate D- and L- enantiomers[110]. In healthy
humans, the plasma clearance ratio ([
99m
Tc][Tc(CO)3(ASMA)]−2/[
131
I]OIH) was 81 ± 3%
for D-ASMA, 20 ± 4% for L-ASMA, and 37 ± 7% for rac-ASMA. In addition, all tracers
exhibited rapid urinary excretion where the percentage of activity in the urine ratio
99m
[
Tc][Tc(CO)3(ASMA)]−2/ [
131
I]OIH was 100 ± 3% for D-ASMA, 80 ± 2% for L-ASMA, and
88 ± 1% for rac-ASMA at three hours p.i.[111] .
12.7 BONE IMAGING AGENTS
99m
The
Tc-bisphosphonates (BP) [
99m
[
Tc]Tc-hydroxymethylenediphosphonate ([
scanning. While these agents have widespread use and established clinical value, there
are some limitations regarding their relatively slow blood clearance, which requires
two hours or longer waiting time before the scan is performed, as well as their in vivo
dissociation due to the low stability of the technetium-phosphonate bond. To overcome
these limitations, new tracers with improved properties were developed by rational
drug design, where suitable robust
nate moiety.
In one eort, aminomethylenediphosphonate (AMDP) was conjugated to L,L-ethylene
dicysteine (EC) chelator, which has been used to form the renal agent [
respective tracer [
of 29.4% ID/g vs. 15.4% ID/g for [
clearance and urinary excretion rates[112].
Alendronate (ALN) was conjugated to the chelators MAG
99m
tive
Tc-tracers were developed, where the HYNIC complex was prepared with tricine
390 Handbook of Radiopharmaceuticals
99m
Tc]Tc-EC-AMDP (Figure12.8) exhibited improved bone uptake in rats
99m
Tc]Tc-methylenediphosphonate ([
99m
Tc]Tc-HMDP) are gold standards for bone
99m
Tc-chelates were conjugated to a bisphospho-
99m
Tc]Tc-MDP at two hours p.i. and comparable blood
and HYNIC, and the respec-
3
99m
Tc]Tc-MDP) and
99m
Tc]Tc-EC. The
OH
+
HOOC
O
N NH
Tc
SS
99m
[
Tc]Tc-EC-AMDP
O
O
–
OH
O
O
OH
P
OH
N
OH
P
H
OH
O
O
O
N N
Tc
N
S
99m
[
Tc]Tc-MAG3-ALN
O
OH
OH
O
P
OH
OH
P
O
NH
OH
O
N
N
OC
n=2: [
n=3: [
O
N
NH
2
Tc
CO
CO
99m
Tc][Tc(CO)3(pzNN-PAM)],
99m
Tc][Tc(CO)3(pzNN-ALN)]
OH
P
OH
N
H
OH
n
P
OH
O
+
N
N
OC
99m
Tc][Tc(CO)3(DPzA-ALN)]
[
HO
N
Tc
CO
OH
OH
OH
P
O
P
OH
O
N
N
CO
OH
N
CO
OH
O
P
OH
OH
P
OH
O
N
N
Tc
OC
CO
99m
Tc][Tc(CO)3(DPA-DABP)]
[
99m
Tc]Tc- MAG3-
HO
O
HO
P
HO
HO
P
HO
O
99m
Tc][Tc(CO)3(ALN-pzNN)]
[
Figure 12.8 Structures of
O
H
N
N
OC
N
NH
Tc
CO
99m
+
NH
CO
2
99m
Tc][Tc(CO)3(DPA-ALN)]
[
OC
N
N
Tc
CO
Tc-labelled bone imaging agents.
as co-ligand and 3-acetylpyridine (Acpy) as a ternary ligand. The tracers [
ALN (Figure12.8) and [
99m
Tc]Tc-(HYNIC-HBP)-tricine-(3-Acpy) exhibited femur uptake in
rats of 4.23 ± 0.25 and 3.96 ± 0.36% ID/g at one hour p.i., which was comparable to that
99m
of [
Tc]Tc-HMDP 3.16 ± 0.51% ID/g[113]. Furthermore, [
99m
Tc]technetium-tricarbonylBP complexes were developed. The pyrazolyldiamine (pzNN) chelator was conjugated
to AMDP, pamidronate (PAM), and ALN, and the tracers [
99m
and [
Tc][Tc(CO)3(pzNN-ALN)] (Figure12.8) exhibited high bone uptake of 18.3 ± 0.6%
ID/g and 17.3 ± 6.1% ID/g, respectively, comparable to the uptake of [
99m
Tc][Tc(CO)3(pzNN-PAM)]
99m
Tc]Tc- MDP w ith
value 17.1 ± 2.4% ID/g at one hour p.i.[114, 115]. A modied derivative, where ALN was
conjugated to the pyrazolyl moiety of the pyrazolyldiamine chelator via a linker, was
developed, [
ID/g at one hour p.i.[116]. The tracer [
99m
Tc][Tc(CO)3(ALN-pzNN)] (Figure12.8), with high bone uptake of 17.1 ± 3.6%
99m
Tc][Tc(CO)3(DPA-ALN)] (Figure12.8) was developed from the DPA chelator that was conjugated to ALN, which exhibited bone uptake
of approximately 27%–30% ID/g at 6.5 hours p.i., with values comparable to that of
99m
[
Tc]Tc-MDP[117]. Similarly, the dipyrazolylamine (DPzA) chelator was conjugated
to ALN, and the tracer [
uptake of 17.7 ± 3.0% ID/g at one hour p.i.[116]. A series of [
99m
Tc][Tc(CO)3(DPzA-ALN)] (Figure12.8) exhibited high bone
99m
Tc]technetium-tricarbonyl
complexes was developed, where 1-(3-aminopropylamino)ethane-1,1-diyldiphosphonic
acid (DABP) were conjugated to various tridentate chelators. The tracer with the DPA
chelator, [
19.44 ± 1.44% ID/g in comparison to that of [
p.i.[118]. [
99m
Tc][Tc(CO)3(DPA-DABP)] (Figure12.8), exhibited the highest bone uptake of
99m
Tc]Tc-MDP 13.18 ± 1.96% ID/g at one hour
99m
Tc]technetium-tricarbonyl “2+1” complexes of the type [
99m
Tc][Tc(CO)3(bipy)
(im-BP)] were prepared in high yield with the ligands bipyridine (bipy) and imidazole
N
CO
OH
OH
O
P
OH
P
OH
NH
O
Chapter 12:
99m
Tc Radiopharmaceutical Chemistry 391
conjugated to bisphosphonates (im-BP) such as alendronate. These tracers exhibited high
stability as well as skeletal accumulation in mice in scintigraphic studies[27].
12.8.1
99m
Tc-Bombesin-like Radioligands
It is known that the transmembrane mammalian Gastrin Releasing Peptide Receptor
(GRPR or BB
R) is overexpressed in various tumor types, with a high prevalence in
2
prostate and breast carcinomas, but also in small cell lung cancer, renal cell carcinoma,
and gastrointestinal stromal tumors[119]. Bombesin is an amphibian tetradecapeptide
that binds selectively to GRPR. A number of
99m
Tc radioligands targeted for GRPR have
been developed based either on bombesin (BN) and its truncated octapeptide BN(7-14)
or on the decapeptide neuromedin C, which is the fragment Gastrin Releasing Peptide
(GRP) (18-27).
One of the earlier eorts in this area described the development of a BN(7-14) analogue conjugated via the Me
spacer. The tracer [
99m
Tc]Tc- N3S-G-5Ava-BN(7-14) (
Gly-Ser-Cys (N3S) chelator and the 5-aminovaleric acid (5Ava)
2
99m
Tc-RP527) (Figure12.9) developed
was evaluated in prostate and breast cancer patients. The radioligand detected four
out of six breast cancer patients and one out of four prostate cancer patients[120].
Another bombesin analogue, [
Gly-His-Leu-Met-NH
, also exhibited in vivo tumor localization in human breast cancer
2
99m
Tc]Tc-Cys-Aca-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-
patients[121, 122].
Furthermore, a series of [
99m
Tc]Tc-tricarbonyl-BN complexes were developed, where
the Nα-histidinyl acetate (Nα-His-Ac) bifunctional chelator was conjugated to BN(7-
14). The peptide ligand Nα-His-Ac-BN(7-14) as well as the Re complex [Re(CO)
Ac-BN(7-14))] exhibited IC
PC-3 cells[123]. The tracer [
of 4.3 nM and 0.6 nM, respectively, against [
50
99m
Tc][Tc(CO)3(Nα-His-Ac-BN(7-14))] (Figure12.9) was 75% and
(Nα-His-
3
125
I][iodoTyr4]BN in
7% intact at 15 and 120 minutes, respectively, in human plasma stability studies, and its
tumor uptake in PC-3 tumor-bearing mice was low (0.89 ± 0.27% ID/g 30 minutes p.i.). To
improve the properties, various modications were implemented, and the replacement
of the amino acids Leu
13
and Met14 with the non-natural amino acids cyclohexylalanine
(Cha) and norleucine (Nle), respectively, as well as the insertion of spacers with β-amino
acids sequences between the chelator, and the peptide improved the biodistribution prole of the tracers[124–126]. Furthermore, pegylation of BN(7-14)(127) was performed,
and the tracers [
exhibited a signicant increase in their human plasma stability with t
the receptor anity was unaected. The tumor uptake of [
3
β
hLys(PEG5)-βAla-βAla-BN(7-14) [Cha13,Nle14]))] was 3.91 ± 0.44% ID/g 60 minutes p.i. in
99m
Tc][Tc(CO)3(Nα-His(Ac-β3hLys(PEGn)-βAla-βAla-BN(7-14) [Cha13,Nle14]))]
> 24 hours, while
99m
1/2
Tc][Tc(CO)3(Nα-His(Ac-
PC-3 tumor-bearing mice[127]. In another modication, a series of glycated BN analogues
were developed by introducing the glycomimetic, shikimic acid, or glycose on the peptide
spacer by various methods[128, 129]. In the tracer bearing a clickable glucose moiety,
392 Handbook of Radiopharmaceuticals
O
-
L=tricine/TPPTS
HO
O
O
O
N
N
Tc
N
S
H
N
N
H
O
O
H
N
O
H2N
NH
O
H
N
N
H
O
O
H
N
N
H
O
HN
O
N
H
N
N
H
O
S
O
NH
N
H
2
O
99m
[
Tc]Tc-N3S-G-5Ava-BN(7–14),
N
OC
N
N
H
O
NH-BN(7–14)
N
O
Tc
O
CO
O
NH-R
O
N
Tc
N
O
H
99m
Tc-Demobesins
99m
Tc-SARNCs
HN
OC
99m
[
Tc][Tc (CO)3(Na-His-Ac-BN(7–14))],
R=BN(1–14):
R=GRP(18-27):
Figure 12.9 Structures of
99m
Tc-RP527
O
Ser3-BN(7–14)
NH
HN
Tc
OC
99m
[
Tc]Tc(CO)3(Dpr-Ser3-BN(7–14)),
X=H
O, P(CH2OH)
2
N
N
N
L
L
Tc
L
L
99m
[
Tc]TcHYNIC-Aca-BN(7–14),
99m
Tc-bombesin-like imaging agents.
CO
CO
3
NH-Aca-BBN(7–14)
O
X
BN(7–14)
+
N
99m
[
Tc]Tc(CO)3(pz-X-BN(7–14)), X=Gly
Gly-Gly, Ser-Ser-Ser, b-Ala
increased uptake and retention in tumor tissue (3.6 and 2.5% ID/g at 1.5 and 5 hours p.i.,
respectively) was observed[128]. Modications on the chelator were also performed,
and the one with the “click” analogue of histidine, triazole-histidine (Tz H is), resulted in
improved tumor-to-background ratios[130–132].
99m
The [
Tc][Tc(CO)3(Dpr-SSS-BN(7-14)(X)] tracers (Figure12.9) were also developed,
with the bidentate chelator 2,3 diaminopropionic acid (Dpr) conjugated to BN(7-14) via
a triserine spacer (SSS), and water or trishydroxymethylphosphine, P(CH
OH)3, as the
2
monodentate co-ligand X. These tracers exhibited tumor uptake of 3.68 ± 0.92% ID/g at
one hour p.i., when X=water, and 2.68 ± 1.3% ID/g at one hour p.i., when X=P(CH
in PC-3 tumor-bearing mice[133]. Furthermore, a series of [
99m
Tc(CO)3-pz-X-BN(7-14)]
OH)3,
2
conjugates were developed, where BN(7-14) was conjugated via the amine terminal
to the tridentate pyrazolyl-diamine (pz) chelator with spacers X (X=β-Ala, GGG, and
SSS) (Figure12.9). In PC-3 tumor-bearing mice, tumor uptake of 1.76 ± 0.79% ID/g and
1.76 ± 1.20% ID/g at one hour p.i. was obtained for SSS- and GGG-containing radioligands,
N
OC
N
Tc
CO
O
BN(7–14)
X
+
NH
CO
Chapter 12:
99m
Tc Radiopharmaceutical Chemistry 393
respectively[134]. Similarly, a series of [
99m
Tc][Tc(CO)3-DTMA-(X)-BN(7-14)]+ complexes
were developed where BN(7-14) was conjugated to diethylenetriamine monoacetic acid
(DTMA) chelator with the spacers X=β-Ala, GGG, and SSS. All radioligands exhibited high
receptor binding anity as well as high tumor cell uptake in vitro. [
(β-Ala) - BN(7-14)]
+
was further studied in PC-3 tumor-bearing mice, but low tumor uptake
99m
Tc][Tc(CO)3-DTMA-
was observed (0.95 ± 0.15% ID/g at one hour p.i.), probably due to fast elimination[135].
99m
Also, [
Tc][TcO-DADT-BN]-type derivatives were developed, where BN was
conjugated to hexamethyl (Hx) or pentamethyl (Pm) diaminedithiol chelator (DADT) with
1
the pharmacokinetic modier DTPA. The respective tracers [DTPA
Pm-DADT), Tyr
anity for the GRPR (K
4
]BN were developed, where the Pm-DADT analogue exhibited higher
=4.1 ± 1.4 nM) and lower hepatobiliary clearance (in normal
i
, Lys3-[
99m
Tc]Tc- Hx/
mice)[136, 137].
In another approach, a series of BN derivatives were developed with the tetra-
mine chelator 1,4,8,11-tetraazaundecane (Figure12.9): Demobesin 1, N
6
Phe
,Leu-NHEt13,des-Met14]BN(6-14); Demobesin 3, N4-[Pro1,Tyr4]BN(1-14); Demobesin 4,
N
-[Pro1,Tyr4,Nle14]BN(1-14); Demobesin 5, N4-Bzdig-BN(7-14); and Demobesin 6, N4-Bzdig-
4
14
[Nle
]BN(7-14)[138, 139]. Their binding anities were evaluated in PC-3 cells against
125
[
I][iodoTyr4]BN, and the IC50 values were found to be: Demobesin 1, 0.07 ± 0.08 nM;
-Bzdig0,[(D)
4
Demobesin 3, 0.06 ± 0.04 nM; Demobesin 4, 0.15 ± 0.04 nM; Demobesin 5, 0.08 ± 0.05 nM;
and Demobesin 6, 0.60 ± 0.05 nM. The peptide conjugates were radiolabelled with
99m
Tc; their stability study indicated that the radiotracers remained almost intact in
murine plasma after one or two hours of incubation but were metabolized fast in the
kidneys, and the radiometabolites were detected in urine. In PC-3 tumor-bearing mice,
99m
Tc-Demobesins 3 and 4 exhibited high tumor uptake (9–11% ID/g) at one hour p.i.,
with high tumor retention (7–9% ID/g) at four hours p.i.. In the rst-in-human pilot study,
99m
Tc-Demobesin 4 did not detect metastatic prostate cancer; however, in newly diagnosed patients, local disease was visualized[140]. By a similar approach, neuromedin C
was conjugated to the tetramine chelator (demomedin C), and then a series of demomedin C derivatives were developed: [Gly
demomedin C (SARNC2), [dAla
din C (SARNC4), [βAla
24
/Met27]demomedin C (SARNC5), and [Sar24/Met27]demomedin
24
24
/Met27]demomedin C (SARNC1), [dAla24/Met27]
/Nle27]demomedin C (SARNC3), [dAla24/Leu27]demome-
C (SARNC6). The binding anity of Demomedin C was performed by in vitro receptor
autoradiography competition binding assays against the universal radioligand [
[D-iodoTyr
the IC
derivatives were determined by in vitro displacement of [
membranes[141], and the IC
6
,βAla11,Phe13,Nle14]BN(6-14) in human prostate cancer sections for GRPR, and
value was found to be 1.4 ± 0.02 nM. The binding anities of the demomedin C
50
values were 2.03 ± 1.06 nM for SARNC2, 2.96 ± 1.33 nM for
50
125
I][iodo-Tyr4]BN in PC-3 cell
125
I]
SARNC3, 9.29 ± 3.55 nM for SARNC4, 0.28 ± 0.02 nM for SARNC5, and 1.78 ± 0.32 nM for
SARNC6[142]. The highest in vivo murine plasma stability was displayed by the tracer
99m
Tc-SARNC4, which was found to be >50% intact 5 minutes p.i. The tracer
99m
Tc-demome-
din C localized in human PC-3 implants in mice and exhibited tumor uptake of 9.84 ± 0.81%
ID/g at one hour p.i.[141]. From the demomedin C series, the highest tumor uptake was
exhibited by
99m
Tc-SARNC2 with a value of 12.05 ± 1.22% ID/g at four hours p.i.[142].
394 Handbook of Radiopharmaceuticals