Книга_5903_Библиотеки_им_академика_М_И_Перельмана

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Tc-Demotensin6

NH-bAla-Arg-Dab-Pro-Tyr-Tle-Leu

99m

[

Figure 12.14 Structures of

Tc][Tc(CO)3(NT-XI)],

NH-Lys-(yCH2NH)-Arg-Pro-Tyr-Tle-Leu

99m

Tc-labelled neurotensin imaging agents.

(3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid) was introduced to obtain a more hydrophilic peptide; and in NT-XIX, Tyr-11 was replaced by 2,6-dimethyltyrosine (Dmt). All the NT derivatives exhibited high binding anities in human colon adenocarcinoma cell line HT-29, and the dissociation constants (K

) were calculated to be: NT-II, 0.3 ± 0.2 nM;

NT-XI, 0.5 ± 0.3 nM; NT-XII: 2.0 ± 1.6 nM; [NT-XVIII], 4.5 ± 1.7 nM; and NT-XIX: 15.0 ± 6.0 nM. The metabolic stability of the NT derivatives in human plasma at low concentrations (in the nanomolar ranges) showed that NT-II had a biologic T

of a few minutes, NT-XI and

1/2

NT-XII of approximately 21 hours, and NT-XVIII and NT-XIX had very little degradation in 24 hours, respectively. The tumor uptake of NT-II of NT-XII NT-XIX was 0.4 ± 0.1, 4.6 ± 1.2, and 5.2 ± 0.5% ID/g at ve hours p.i. in HT-29 tumor-bearing mice. The uptake of NT-XI and NT-XVIII was approximately 1.7 and <1% ID/g at the same time point, respectively. The derivative NT-XIX appears to have a better metabolic prole in conjunction with its reduced kidney uptake. Human studies of NT-XI exhibited the ability of the NT derivative to detect NT-expressing tumors[230].

In another approach, NT derivatives were conjugated to the acyclic tetramine chela-

tor for [

99m

Tc]dioxotechnetium labelling. The analogues that were developed were the

following:

Demotensin 1: N Demotensin 2: N Demotensin 3: N Demotensin 4: N Demotensin 5: N Demotensin 6: N

-Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH[231]

-Gly-Lysψ[CH2NH]Arg-Pro-Tyr-Ile-Leu-OH,[231]

-Gly-Lysψ[CH2NH]Arg-Pro-Tyr-Tle-Leu- OH[231]

-Gly-Argψ[CH2NH]Arg-Pro-Tyr-Tle-Leu- OH[231]

-(β)Ala-Arg-Dab-Pro-Tyr-Ile-Leu-OH[232]

-(β)Ala-Arg-Dab-Pro-Tyr-Tle-Leu-OH[232]

In these derivatives, similar modications were made to improve their metabolic stability, such as the reduction of the Arg-Arg bond in Demotensin 4 and its replacement with lysine in Demotensin 2 and 3. Also, the replacement of isoleucine with tert-leucine in Demotensins 3, 4, 6 was performed. In Demotensins 5 and 6, the 2,4 diaminobutyric acid replaced Arg 9. All the Demotensin derivatives exhibited high binding anities in the HT-29 cell line, and the IC

values of Demotensin 1–6 against [

125

I-Tyr3]NT were calculated to be 0.32 ± 0.02, 0.41 ± 0.02, 1.50 ± 0.01, 0.85 ± 0.07, 0.03± 0.01 and 0.08 ± 0.02 nM, respectively. The

99m

Tc-Demotensins were evaluated for their in vivo biodistribution

Chapter 12:

99m

Tc Radiopharmaceutical Chemistry 405

properties and their metabolic stability. Metabolic stability in murine plasma showed that

[

Tc]TcN-PNP3-Cys-Gly-CCK8

[ [ [ Glu

99m

Tc-Demotensins 3 and 4 were stable up to one hour, while

shorter half-life of t

Similarly,

99m

values for

99m

Tc-Demotensin 6 was >90% stable for two hours in murine plasma, whereas

Tc-Demotensin 5 degraded with a half-life of t

99m

Tc-Demotensins 3 and 4 were 3.52 ± 0.66 and 4.94 ± 0.52% ID/g at one hour

= 20–25 minutes and

1/2

99m

Tc-Demotensin 1 of t

∼ 15 minutes. The tumor uptake

1/2

99m

Tc-Demotensin 2 had a

= 3–5 minutes[231].

1/2

p.i., respectively, in HT-29 tumor-bearing mice, while in human NTS1-R-expressing WiDr tumor-bearing mice, their tumor uptake was found to be 3.95 ± 0.64 and 4.72 ± 0.72, % ID/g

at one hour p.i., respectively[231]. Tumor uptake in WiDr-bearing mice for

99m

Tc-Demoten-

sins 5 and 6 were 1.68 ± 0.15 and 4.30 ± 0.45% ID/g at one hour p.i., respectively[232]. A pilot study in human patients revealed that

99m

Tc-Demotensin 6 (Figure12.14) could

detect tumors in brain metastases[233].

12.8.7 CCK-2 Receptor Imaging Agents

The overexpression of cholecystokinin (CCK) type-2 receptors (or B receptors or gastrin receptors) has been observed in the majority of medullary thyroid carcinomas as well as in some other carcinomas (e.g. small-cell lung and ovarian). In the eorts to

develop

Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH (CCK-8: Asp-Tyr-Met-Gly-Trp-Met-Asp-PheNH [D-Glu chelator (Nα-His-Ac-MG), and the respective tracers [ Tc-EDDA-HYNIC-MG (Figure12.15) and [ stability in serum. Competition experiments of the unlabelled peptide conjugates on AR42J membranes versus [ conjugates under study. In AR42J tumor-bearing nude mice, the highest tumor uptake was observed in the tracer [ Tc-Tricine-HYNIC-MG (2.2% ID/g) and then [ four hour s p.i., while the kidney uptake observed was 101.0% ID/g, 53.8% ID/g, and 1.8% ID/g, respectively[234]. To improve kidney uptake, the shortened peptide analogue, which lacks Glu

99m

Tc-probes for CCK2R imaging, the minigastrin (MG: Leu-Glu-Glu-Glu-Glu-Glu-

) peptide and its derivatives or the cholecystokinin

) peptide were employed. The peptide

]MG was conjugated to HYNIC (HYNIC-MG) and to the Nα-histidinyl acetate

125

I][iodoTyr12]-gastrin I showed a high CCK2R anity for all

99m

Tc]Tc-EDDA-HYNIC-MG (8.1% ID/g), followed by [

2–6

, [HYNIC0,DGlu1,desGlu

99m

Tc]Tc-Tricine-HYNIC-MG, [

99m

Tc]Tc(CO)3(Nα-His-Ac-MG) exhibited high

99m

Tc]Tc(CO)3(Nα-His-Ac-MG) (1.2% ID/g) at

2–6

]MG (HYNIC-MG11), was developed. The tracer

99m

Tc]

NH-R

99m

Tc]TcHYNIC-MG, MG: R=[DGlu1]MG ,

99m

Tc]TcHYNIC-MG11:R=[DGlu1,desGlu

99m

Tc]TcHYNIC-cyclo-MG1: cyclo

2-6

,desGlu

,D-Lys9]MG, L=EDDA/tricine,

Figure 12.15 Structures of

2-6

]MG

1,9

[g-D-

99m

Tc-labelled CCK-2 receptor imaging agents.

N H

R=[Gln1]gastrin: R=[Gly

406 Handbook of Radiopharmaceuticals

NH-R

-D-Glu1]MG:

99m

Tc-SG6

99m

Tc-Demogastrin2

99m

N H

NH-Gly-CCK

99m

[

Tc]Tc-EDDA-HYNIC-MG11 (Figure12.15) synthesized exhibited serum stability of 89.4%

at 24 hours (the respective stability of [

99m

Tc]Tc-EDDA-(HYNIC-MG) was 90.5% at 24 hours). A high binding anity of HYNIC-MG11 for the CCK2R was displayed in displacement studies against [

125

I][iodoTyr12]-gastrin I, with IC50 value <2 nM as well as [

(HYNIC-MG11) exhibited in a saturation assay K

of 3.97 nM. [

99m

Tc]Tc- ED DA-(HYNIC- M G11)

99m

Tc]Tc- ED DA-

exhibited unaltered tumor uptake of 7.11 ± 0.22 %ID/g at four hours p.i., while kidney uptake was reduced by 98% in comparison with the respective biodistribution results of

99m

[

Tc]Tc- ED DA-(HYNIC- M G)[235].

Also, the development of tetramine derivatives of minigastrin was reported. Demogastrin derivatives 1–3 contain the following sequences: Demogastrin 1, [N MG; Demogastrin 2, N

0–1

,Gly0-D-Glu1]MG; and Demogastrin 3, [N′

,D-Glu1]MG, with the

,D-Glu1]

tetramine ligand N,N′,N″,N′′′-tetra-(tert-butoxycarbonyl)-6-X-1,4,8,11-tetraazaundecane

(where in N

respective dioxotechnetium complexes

; X=carboxy and N′4; X=p-(carbomethoxy)acetyl]aminobenzyl)[236]. The

99m

Tc-Demogastrin 1–3 prepared were stable

for two hours in mouse plasma, but complete degradation was observed in urine. The

99m

carrier-added tracers

ities in AR42J cell membranes, and their K and 1.01 ± 0.09 nM, respectively. Tumor uptake values of

99g

Tc/

Tc-Demogastrin 1–3 were evaluated for their binding an-

values were found to be 1.05 ± 0.13, 1.02 ± 0.07,

99m

Tc-Demogastrins1–3 were

6.13 ± 3.28, 5.50 ± 0.85, and 4.20 ± 1.22 %ID/g at one hour p.i., respectively, in AR42J tumorbearing mice. At the same time, high kidney uptake values of 78.97 ± 1.60, 83.92 ± 14.45, and 78.18 ± 11.85% ID/g, respectively, were observed.

99m

Tc-Demogastrin 2 (Figure12.15) was also evaluated in a medullary thyroid carcinoma patient, where all the known lymph node lesions were clearly detected[236]. Similarly, two other gastrin radioligands were developed–the full-length [ truncated [

99m

Tc][Tc-N4-D-Glu10]gastrin(10 –17) (

99m

Tc][Tc-N4-Gln1]gastrin (

99m

Tc-SG6) (Figure12.15) and the

99m

Tc-DG4)–and were compared to

99m

Tc-

Demogastrin 2. Competition binding studies of the ligands SG6, Demograstrin 2 and DG4 in A431-CCK2R(+) cell membranes against [ and the IC

values of the ligands were found to be 9.3 ± 0.9, 10.7 ± 1.3, and 0.9 ± 0.1 nM,

125

I][iodoTyr12,Leu15]gastrin were performed,

respectively. The tumor uptake of the radiotracers in A431-CCK2R(+) xenografts was found to be 12.89 ± 4.69% ID/g for and 0.99 ± 0.13% ID/g for

99m

Tc-Demogastrin 2, 10.25 ± 3.51% ID/g for

Tc-DG4 at one hour p.i.. The in vivo mouse plasma stability was measured 5 minutes p.i. and found to be: intact; and

99m

Tc-DG4, 10% intact. However, prior administration of neutral endopepti-

99m

Tc- Demogastrin 2, 60% intact;

99m

Tc-SG6,

99m

Tc-SG6, 40%

dase (NEP) and angiotensin-converting enzyme (ACE) inhibitors phosphoramidon (PA) and Lisinopril (Lis), respectively, signicantly increased the tracers’ stability, as follows:

99m

Tc- Demogastrin 2, 85% intact;

tumor uptake was also improved to 18.21 ± 5.97% ID/g (PA + Lis) for

18.46 ± 3.56% ID/g (PA only) for four hour s p.i.. The kidney uptake of

The development of cyclized MG was also reported, where the tracers [ HYNIC-cyclo-MG1 (cyclo-MG1: cyclo HYNIC-cyclo-MG2 (cyclo-MG2: cyclo

99m

Tc-SG6, 70% intact; and

99m

Tc-SG6, and 8.91 ± 1.61% ID/g (PA + Lis) for

99m

Tc-Demogastrin 2 and

1,9

[γ-D-Glu1,desGlu

1,9

[γ-D-Glu1,desGlu

99m

Tc-DG4, 80% intact. Their

99m

Tc-SG6 was high[237].

2–6

,D-Lys9]MG) and [

2–6

,D-Lys9, Nle11]MG) were

Tc-Demogastrin 2,

99m

Tc-DG4 at

99m

Tc]Tc- ED DA-

99m

Tc]Tc- ED DA-

developed (Figure12.15). The in vitro stability in human plasma was found to be

Chapter 12:

99m

Tc Radiopharmaceutical Chemistry 407

88.6–97.6% intact peptide after 24 hours of incubation. The dissociation constant (KD) of tracers [

99m

Tc]Tc-EDDA-HYNIC-cyclo-MG1 and [ to be 19.1 and 21.2 nM, respectively. The tumor uptake values of [ cyclo-MG1 and [

99m

Tc]Tc-EDDA-HYNIC-cyclo-MG2 were 3.61 and 3.17% ID/g one hour p.i.,

99m

Tc]Tc-EDDA-HYNIC-cyclo-MG2 was found

99m

Tc]Tc- ED DA-HYNIC-

respectively[238].

Using a dierent approach, the natural octapeptide CCK8 was conjugated to a tet-

radentate (PN

GC), and the respective [ yield. Its binding anity was K

S) chelator N-(N-(3-diphenylphosphinopropionyl) glycyl)cysteine (Phos-

99m

Tc][TcO(Phos-GC-CCK8)] complex was synthesized in high

=32.0 ± 5 nM in A-431 cells, its tumor uptake in A-431

tumor-bearing mice was 2.01 ± 0.80% ID/g at two hours p.i., and it displayed both renal and hepatobiliary excretion[239]. The development of nitridotechnetium complexes for CCK2R was reported as well, where CCK8 was derivatized with a cysteine residue (Cys-Gly-CCK8) that was used in the tracer [

99m

Tc][TcN(N,S-Cys-Gly-CCK8)(PNP3)]+ (PNP3=N,N-bis(dimethoxypropylphosphinoethyl)methoxyethylamine) (Figure12.15). Its binding anity in A-431 cells was found to be K

=19.0 ± 4.6 nM (B

∼ 1 06 sites/cell), and

max

its tumor uptake in A-431 tumor-bearing mice was <1 %ID/g at one hour p.i., while high intestinal activity was observed[240].

 

The vitamin folic acid has been eectively applied for the development of diagnostic radiopharmaceuticals to target folate receptor (FR)-positive tumors such as ovarian, non- small-cell lung, endometrial, breast, and renal cell carcinoma. One of the early eorts describes the conjugation of folate to DTPA chelator for standard

99m

as for [

99m

[

Tc][Tc(CO)3]+-labelling. Intravenous administration of [

Tc]Tc(CO)3(DTPA-folate) to athymic mice bearing KB cell tumor xenografts resulted in tumor uptake of 2.9 ± 0.8 and 3.3 ± 0.2% ID/g at four hours p.i., respectively. Furthermore, high kidney uptake of 21 ± 3 and 46 ± 5% ID/g in each kidney was observed at the same time point, due to physiologic FR presence in the renal tubules[241, 242]. Also, a folate-containing peptide with the sequence pteroic acid (Pte), D-Glu, β-diaminopropionic acid, Asp, and Cys (EC20) was developed, where the latter three amino acids function as

a tetradentate (NNN S) chelator for

99m

Tc-labelling[243].

99m

of two oxotechnetium(V) complexes characterized as syn and anti isomers (Figure12.16). The FR binding anity of vivo tumor uptake of

99m

Tc-EC20 in KB cells was measured to be KD=3.2 nM. The in

99m

Tc-EC20 in mice bearing FR-positive M109 cells was 17.2 ± 1.02% ID/g at four hours p.i., with kidney uptake of 138 ± 12.4% ID/g at the same time point. Currently,

99m

Tc-EC20 (

99m

Tc-etarfolatide, Endocyte Inc.) is being studied as a companion

diagnostic imaging agent to the therapeutic folate-targeted agent vintafolide in multiple

clinical trials[244].

A series of [

99m

Tc][Tc(CO)3-folate] complexes was developed (Figure12.16), where

folate was conjugated to the PAMA tridentate chelator via a hexylamine linker on

either the γ- or α-glutamate, [ α-folate)]; and by a similar design, [

99m

Tc][Tc(CO)3(PAMA-γ-folate)] and [

99m

Tc][Tc(CO)3(PAMA-pteroate)], was synthesized

99m

Tc-labelling as well

99m

Tc]Tc-DTPA-folate and

Tc-EC20 consists of a mixture

99m

Tc][Tc(CO)3(PAMA-

408 Handbook of Radiopharmaceuticals

O COOH

A-folate

H2N

N H

99m

[

Tc]Tc-EC20

O COOH

99m

[

Tc]Tc(CO)3(His-folate), X=C

99m

[

Tc]Tc(CO)3(TzHis-folate), X= N

Figure 12.16 Structures of

COOH

H N

99m

Tc-labelled folate imaging agents.

N H

COOH

H2N

99m

[

H2N

Tc]Tc-PAMA-folate

N H

99m

[

Tc]Tc-IDA-folate

[

99m

Tc]Tc-DP

lacking glutamate[245]. The

99m

Tc-folates were also prepared in a kit-like method, where the PAMA conjugates were placed in a kit with the Isolink components, with very high radiochemical yields (>92%). The binding anities of [

99m

[

Tc][Tc(CO)3(PAMA-α-folate)], and [

determined (by the Rosenthal analysis) with K

99m

Tc][Tc(CO)3(PAMA-pteroate)] in KB cells were

99m

Tc][Tc(CO)3(PAMA-γ-folate)],

values of 2.09, 2.51, and 14.52 nM, respec-

tively. Biodistribution studies in KB-tumor-bearing mice revealed tumor uptake of

2.33 ± 0.36, 1.24 ± 0.19, and 0.43 ± 0.17% ID/g at four hours p.i. for the three radiofolates, respectively, with kidney uptake of 18.5 ± 0.7, 12.4 ± 1.9, and 3.3 ± 0.4% ID/g, respectively, and signicant hepatobiliary clearance for all the tracers[246]. Importantly, selective FR-blockade in the kidneys was accomplished after administration of antifolates prior to radiofolate administration, while the FR-mediated uptake of radioactivity in KB tumor xenografts was retained[247]. Similar results were obtained with the tracers

99m

[

Tc][Tc(CO)3(IDA-γ-folate)] and [

99m

Tc][Tc(CO)3(DPA-γ-folate)], with tumor uptake in KB- bearing mice of 2.67±0.27 and 0.94±0.10% ID/g at four hours p.i., respectively, and with high cell binding of 40–55% in KB cells as well[248]. In a dierent design, N(τ )-histidinefolate (His-folate) and its isostructural click 1,2,3-triazole (TzHis-folate) analogue were synthesized, where the γ-glutamate of folate was conjugated via a butylamine linker to the chelator, and the respective [

99m

Tc]Tc(CO)3(His-folate) and [

99m

Tc]Tc(CO)3(TzHis-folate)

tracers were prepared (Figure12.16). Their tumor uptake in tumor-bearing mice was

4.29±0.67 and 4.84±0.10% ID/g at four hours p.i., while their accumulation in the kidney was 24.56±3.17 and 27.33±3.61% ID/g, respectively[249].

In a recent report, [

by ligand-exchange reaction from [

99m

Tc]Tc-folate-GGCE (folate-Gly-Gly-Cys-Glu) was developed

99m

Tc]Tc-tartrate at >95% radiolabelling eciency. The structure of the technetium complex was not described, but it is assumed that the tetrapeptide, GGCE, is the

99m

Tc-chelator. Its binding anity (KD) was measured to be

Chapter 12:

99m

Tc Radiopharmaceutical Chemistry 409

5.19 nM. The KB-tumor uptake of

99m

Tc-folate-GGCE was 16.4, 23.2, and 17.6% ID/g, at one, two, and four hours p.i., respectively, and the kidney uptake was 57.04±18.58 %ID/g at four hour s p.i.[250]. Also, the [ pared by direct labelling at >95% radiochemical yield[251]. The binding anity (K

99m

[

Tc]Tc-TEPA-folate was found to be 5.00± 0.06, 27.46± 0.01, and 25.85± 0.005 nM in

99m

Tc]Tc-tetraethylenepentamine(TEPA)-folate was pre-

) of

KB, U-87MG, and MDA-KB-468 cells, respectively. The tumor uptake of the tracer in KB tumor-bearing mice was 4.26± 1.3% ID/g, kidney uptake was 16.0 ±1.2% ID/g, and liver uptake was 16.0 ±2.0 %ID/g at four hours p.i.[251]. Furthermore, [

99m

Tc]Tc- (DO3A-EA)folate was synthesized by direct labeling at high eciency, where DO3A-EA is 1,4,7-tris (carboxymethyl)-10-(4-aminoethyl)-1,4,7,10-tetraazacyclododecane linked to folic acid via its γ-carboxyl group. The in vitro receptor binding anity (K

) was found to be 4.2 ± 0.8,

22.54 ± 0.002, and 16.68 ± 0.01 μM in KB, U-87MG, and OAW, respectively. KB tumor uptake in tumor-bearing mice was 6.26 ± 0.4 at four hours p.i.. Both renal and hepatobiliary clearance were observed[252].

12.8.9

The development of a SPECT tracer based on tive, given the wide usefulness of the PET agent 2-deoxy-2-[ of [

99m

Tc-Labelled Glucose Derivatives

99m

Tc-labelled glucose derivatives is attrac-

F]uoro-d-glucose. Series

99m

Tc][Tc(CO)3-glucose] tracers were developed for this purpose by rational drug design. Glucose derivatives were designed for conjugation to a tridentate chelator such as iminodiacetate (IDA) at positions, C-1, C-2, C-3, and C-6 (Figure12.17). The C-1 glucose derivatives were separated by an ethyl spacer from IDA[253], while the C-2 and C-6[254] derivatives had C3, C8, and triethyleneglycol spacers. Furthermore, glucose derivatives were designed for conjugation to histidine, bisimidazolylamine, and PAMA chelators at position C-3, as well[255]. The tracers [

99m

Tc][Tc(CO)3(L-Glucose)] (L=IDA, His, PAMA) were evaluated in a dose-dependent manner for their ability to be transported via GLUT1 glucose transporters in HT29 colon cancer cells, where their uptake was found not to be mediated by GLUT1. The analogous Re-complexes were evaluated for competitive inhibition of hexokinase, where only the C-2 derivatized glucose complexes with extended spacer functionalities were found to be active; in particular, Re(CO) C8-glucose)] and [Re(CO)

(2-deoxyglucose-(PEG)3IDA)] exhibited Ki values of 5.8 ± 0.9 mM

(2-IDA-

and 0.25 ± 0.01 mM, respectively. The competitive inhibitors, though, were not recognized as substrates of hexokinase[256]. Similar C-1 glucose derivatives [ glucose)] and [

99m

Tc][Tc(CO)3(1α-IDA-2-deoxyglucose)] were evaluated in B16F1 melanoma-

99m

Tc][Tc(CO)3(1β-IDA-

bearing mice, where low tumor uptake was observed of 0.31 ± 0.23 and 0.40 ± 0.28% ID/g at one hour p.i., respectively[257].

Another series of [

99m

Tc]Tc(CO)3-glucose and -glucosamine tracers were developed, conjugated at the C-1 or C-2 position to various chelators[258, 259] including hydroxypyridone[24], DPA, PAMA, and Schi-based chelators[260–263], as well as the cyclopentadienyl chelator (Figure12.17)[264]. From these complexes, the Re analogue Re(CO)

(2-glucosamine-Cp) was evaluated for competitive inhibition of hexokinase,

which exhibited Ki=330 ± 70 μM, although the complex was not recognized as a substrate

410 Handbook of Radiopharmaceuticals

99m

[

99m

Tc]Tc(CO)3(1a-IDA-2-deoxyglucose)

Tc]Tc(CO)3(3-His-glucose)

Tc]Tc(CO)3(2-DPA-glucosamine)

Figure 12.17 Structures of

99m

[

Tc]Tc(CO)3(1b-IDA-glucose)

Tc]Tc(CO)3(3-PAMA-glucose)

99m

[

Tc]Tc(CO)3(2-NNO-(CH2)n-glucosamine)

Tc-labelled glucose derivatives.

[

99m

O CO

99m

[

Tc]Tc(CO)3(2-IDA-X-glucose)

X=(CH

99m

[

Tc]Tc(CO)3(6-IDA-glucose)

N H

, (CH2)8, CH2CH2(OCH2CH2)2,

2)3

99m

[

Tc]TcECDG

N H

99m

[

99m

[

99m

[

Tc]Tc(CO)3(3-IDA-glucose)

99m

[

Tc]Tc(CO)3(2-cp-glucosamine)

Tc]Tc-4AcTG,4AcTG=2,3,4,6-Ac-1-thioglucose, Tc]Tc-1-TG, 1-TG=1-thioglucose

TGGT

of hexokinase[264]. The tracers [

99m

Tc][Tc(CO)3(2-glucosamine-NNO)] with NNO-type chelators exhibited no specic GLUT1 transport in LCC6-HER2 human breast cancer cells. In addition, the Re analogues were not recognized as substrates of HK; however, Re(CO)

(2-glucosamine-CO-C7-NNO) behaved as a competitive inhibitor of HK with Ki of

70 ± 20 μM[260]. Furthermore, the tracer [

99m

Tc][Tc(CO)3(2-glucosamine-DPA)] was eval-

uated in B16F10 murine melanoma tumor-bearing mice and exhibited tumor uptake of

0.47 ± 0.09% ID/g at two hours p.i.[265]. The tracer [

99m

Tc][Tc(CO)3(TzHis-C4-2-glucose)] was developed by “click” conjugation from a C-2 glucose derivative with a butyl spacer. The tracer was administered in lung carcinoma-bearing mice, and it exhibited tumor uptake values of 0.55 ± 0.05 and 0.35 ± 0.01% ID/g at one and two hours p.i., respectively[266].

Using a dierent approach, the tracer [

D-glucosamine) ([

99m

Tc]Tc-ECDG) (Figure12.17) was developed, and in vitro studies

showed that its cellular uptake was mediated by a

99m

Tc]oxotechnetium-ethylenebis(L-cysteinyl-

d-glucose transport mechanism and

that ECDG was a substrate of hexokinase (HK)[267]. Biodistribution in human A549 lung cancer-bearing mice showed a low tumor uptake of [

at four hour s p.i.. Furthermore, it was shown that [

99m

Tc]Tc-ECDG of 0.41 ± 0.16% ID/g

99m

Tc]Tc-ECDG was capable of assess-

ing the therapeutic response of tumor-bearing mice post-treatment[268]. An initial

Chapter 12:

99m

Tc Radiopharmaceutical Chemistry 411

clinical trial in seven human patients showed that the tumor uptake of [ three to four times that of normal tissue uptake[269]. Also, the tracer [ D-isomer-glucosamine (DG) was reported. In vitro, it was shown that [ DG and [ human breast tumor-bearing mice, the tumor uptake of [

F]FDG exhibited similar uptake values in MCF-7 tumor cells. In vivo, in MCF-7

99m

Tc]Tc–DTPA–DG and [18F]FDG

99m

Tc]Tc-ECDG was

99m

Tc]Tc- DTPA-D

99m

Tc]Tc– DT PA–

was 1.59 ± 0.04 and 1.42 ± 0.12% ID/g, and the tumor-to-blood ratio was 3.24 ± 0.65 and

7.12 ± 2.12 at four hours p.i., respectively[270]. Furthermore,

99m

Tc-1-thio-β-d-glucose ([ direct labeling in high radiochemical yields (Figure12.17). The ated for their tumor cell uptake in comparison to [

99m

Tc-labelled thioglucose (TG) analogues were developed; in particular,

99m

Tc]Tc1-TG) and [

99m

Tc]Tc-5- thio- d -glucose were prepared by

99m

Tc tracers were evalu-

F]FDG, where they exhibited tumor uptake with a mechanism analogous to that of glucose, although the tracers exhibited higher accumulation in the cell membranes compared to [

F]FDG[271, 272]. [

99m

Tc]Tc-1-TG was evaluated as an imaging tool for the diagnosis of joint inammatory disorder[273]. Similarly, 1-thio-β- 99m by ligand exchange from

d-glucose 2,3,4,6-tetra-acetate (4AcTG) was labelled with technetium-

99m

Tc-tartrate. [

99m

Tc]Tc-4AcTG exhibited high uptake in bacteria and tumor cells expressing GLUT1 transporters, as well as in vivo uptake in infection (Staphylococcus aureus) and RMA lymphoma in mice, with values of 1.81 ± 0.11 and

3.54 ± 0.12 %ID/g at two hours p.i., while the uptake values of [

F]-FDG were 0.68 ± 0.19

and 0.93 ± 0.26% ID/g, respectively[274].

In another study, three

(S-DG), mercaptoacetyltriglycinyl-

d-deoxyglucose (MAMA-BA-DG), were labelled by ligand exchange from

tate in high radiochemical purities. Biodistribution of [

99m

and [

Tc]Tc-MAMA-BA-DG was performed in MA891 breast tumor-bearing mice, where

d-glucosamine (DG) derivatives, N-thioacetyl-d-glucosamine

d-glucosamine (MAG

-DG), and MAMA-butanamide-

99m

Tc]Tc-S - DG , [

99m

Tc-glucohep-

99m

Tc]Tc- MAG3-DG,

their tumor uptake was 1.06 ± 0.18, 0.82 ± 0.06, and 0.21 ± 0.03% ID/g at four hours p.i., respectively, while the respective tumor-to-blood ratio at the same time-point was

0.82 ± 0.15, 0.94 ± 0.13, and 0.94 ± 0.16[275]. In another study, two glucose derivatives were prepared by conjugation of the MAG

of β-

d-glucosamine (DG)[276] and β-d -glucopyranose-4-phenylamine (PhDG)[277].

The respective tracers [

99m

Tc]Tc- MAG3-DG and [

chelator at the glucopyranose C-1 position

99m

Tc]Tc- MAG3-PhDG were evaluated in

Ehrlich tumor-bearing mice with tumor uptake of 0.79 ± 0.14 and 0.50 ± 0.04% ID/g for

99m

[

Tc]Tc- MAG3-DG and [

99m

Tc]Tc- MAG3-PhDG at two hours p.i., respectively[276]. The HYNIC-glucosamine (HYNIC-DG) derivative was labelled by two dierent methods, and the respective tracers [

99m

Tc]Tc-(HYNIC-DG)-Tricine-TPPTS and [

99m

Tc]Tc- (H Y N IC-

DG)-EDDA were produced. The tumor uptake in S180 murine sarcoma-bearing mice of

99m

Tc]Tc-(HYNIC-DG)-Tricine-TPPTS and [

99m

Tc]Tc-(HYNIC-DG)-EDDA was 0.44 ± 0.13 and

0.46 ± 0.06% ID/g at two hours p.i., respectively[278]. Dithiocarbamate-Glucose-1 derivatives were prepared by “click” conjugation of a C-1 derivatized glucose, which formed the respective [

99m

Tc][TcN(dithiocarbamate-glucose-1)2] tracers. The tracers were evaluated in S180 murine sarcoma-bearing mice, and the maximum tumor uptake was found for the tracer with the longer propyl linker of 4.30 ± 0.61% ID/g with blood activity of 4.15 ± 0.53% ID/g at two hours p.i.[279].

412 Handbook of Radiopharmaceuticals

12.8.10

′-NNO-thymidine)

99m

Tc-Labelled Thymidine Derivatives

Targeting thymidine kinase with radiotracers has been used as an approach to diagnose cancers. In addition, imaging of the non-invasive herpes simplex virus type-1 thymidine kinase (HSV1-tk) gene expression has wide interest for research on gene therapy and for conrmation of gene delivery.

In a series of thymidine analogues developed, 5′-carboxamide thymidine was conjugated to the chelators IDA and PAMA with various spacers of length 0–30 Å, which were complexed with the [M(CO)

]+ core (M=

99m

Tc, Re) (Figure12.18). The Re-complexes were tested in vitro for their ability to inhibit human cytosolic thymidine kinase (TK) with Ki values ranging from 4.4 to 334 μM[280, 281]. By replacing the 5-methyl moiety of thymidine with a 5-ethyl moiety, the respective Re(CO)

(IDA-5′-carboxamide 5-ethyl-

2′-deoxyuridine) complex was found to be a selective competitive inhibitor of HSV1-TK (Ki=4.56 μM)[282]. In addition, a series of N3- and C3′-functionalized thymidine ana- logues conjugated by various spacers with tridentate chelators that formed neutral, anionic, and cationic [M(CO)

]+ (M=

99m

Tc, Re) chelates were developed (Figure12.18). A series of N3-functionalized thymidine analogues linked by various spacers to tridentate chelators that form neutral chelates with [Re(NO)(CO) Re complexes, as well as some of the

99m

Tc tracers, were evaluated as potential substrates

]2+ were prepared. The respective

for hTK1 by monitoring the formation of the monophosphorylated product, where it was shown that all the complexes were substrates to the enzyme, with the C3′-functionalized thymidine analogues exhibiting higher anity for the enzyme[283–286]. In vitro cell internalization experiments performed in a human neuroblastoma SKNMC cell line revealed low uptake of the

99m

Tc tracers, dependent on their lipophilicity; hence it was assumed that they are taken up by diusion rather than by facilitated transport[283]. A series of thymidine analogues that were functionalized at positions C5′, C2′, and N3 were linked by various spacers to dipicolylamine and complexed with [Re(CO)

]+. Also,

a series of N3-functionalised thymidine derivatives linked to bis(quinolin-2-ylmethyl) amino and bis(thiazol-4-ylmethyl)amino tridentate chelators were developed. The Recomplexes were tested against A549 lung carcinoma cell line for their cytotoxicity, and

99m

[

Tc]Tc(CO)3(C5′-IDA-thymidine) [

H N

99m

Tc]Tc(CO)3(N3-TzHis-thymidine)

H2N

Figure 12.18 Structures of [M(CO)3]-thymidine derivatives, M=

Chapter 12:

99m

Tc or Re.

99m

[

Tc]Tc(CO)3(C3

Tc Radiopharmaceutical Chemistry 413

some of these derivatives were found to be quite potent, in particular the N3- and C5′-

functionalized derivatives, while low inhibition of TK1 was displayed[287, 288].

Using a dierent approach, a [

99m

Tc]oxotechnetium-MAMA-propyl-N3-thymidine derivative was developed; however, it exhibited a low anity for TK1 and low tumor uptake in vivo in a radiation-induced brosarcoma (RIF) tumor mouse model[289].

12.8.11 Estrogen Receptor Imaging Agents

The development of tors (ERs) overexpressed in ER-positive tumors is of importance in nuclear medicine,

especially for the diagnosis of breast cancers. A number of organometallic technetium and rhenium [M(CO) oped, with various chelators, such as a bidentate dithioether (SS) system, a tridentate dithioether-carboxylate (SSO) system, PAMA, and pyrazolyldiamine (pzNN), as well as cyclopentiadienyl (Figure12.19)[35, 290–292]. The pyridine-2-yl-hydrazine (HYPY) ligand was conjugated to 17α-ethynylestradiol, and the respective Re(CO) plex was evaluated for its relative binding anity (RBA) to the estrogen receptor, and high ER binding was displayed (RBA=38%)[293]. The respective pyridin-2-yl-hydrazine acetic acid (NNO) tridentate chelator was conjugated to 17α-ethynylestradiol, and the analogous Re(CO) eects in ER binding were evaluated after hydrogenation of the triple bond of the complex Re(CO)

(NNO-E17) to its double-bonded and single-bonded analogues, where it

was shown that the Z-ethenyl (double-bonded) derivative exhibited higher binding to ERβ (RBA=24%)[294]. Preclinical evaluation of the tracer [ (Figure12.19) in tumor-bearing mice exhibited low but specic uptake in estrogen receptor-expressing tumors (0.67% for MCF-7 tumors and 0.77% for endometrial tumors at

three ho urs p.i.)[295].

99m

Tc-labelled imaging agents for the detection of estrogen recep-

]+-complexes (M=Re,

(NNO-E17) complex exhibited RBA=20% to ERα[294]. The linkage

99m

Tc) of 17α-ethynylestradiol have been devel-

(HYPY-E17) com-

99m

Tc]Tc(CO)3(NNO - E17)

Figure 12.19 Struc-

tures of [M(CO)

estradiol derivatives,

99m

M=

Tc or Re.

99m

[

Tc][Tc(CO)3(NNO-ethynyl-E17)]

Re(CO)3(cp-tamoxifen-OCH2CH2NMe2)

414 Handbook of Radiopharmaceuticals

99m

[

Tc][Tc(CO)3(cp-ethynyl-E17)]

Re(CO)

(aryl-cp) for ER

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