Rational design of NT-PSMA heterobivalent probes for prostate cancer theranostics
Targeting the prostate-specific membrane antigen (PSMA) with radiopharmaceuticals for imaging and/or therapy has demonstrated significant advancement in the management of prostate cancer patients. However, PSMA targeting remains unsuccessful in prostate cancers with low expression of PSMA, which acc...
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| Vydané v: | RSC medicinal chemistry Ročník 15; číslo 12; s. 4153 - 4158 |
|---|---|
| Hlavní autori: | , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
CAMBRIDGE
Royal Soc Chemistry
16.09.2024
Royal Society of Chemistry RSC |
| Predmet: | |
| ISSN: | 2632-8682, 2632-8682 |
| On-line prístup: | Získať plný text |
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| Shrnutí: | Targeting the prostate-specific membrane antigen (PSMA) with radiopharmaceuticals for imaging and/or therapy has demonstrated significant advancement in the management of prostate cancer patients. However, PSMA targeting remains unsuccessful in prostate cancers with low expression of PSMA, which account for 15% of cases. The neurotensin receptor-1 (NTS
1
) has been highlighted as a suitable oncotarget for imaging and therapy of PSMA-negative prostate cancer lesions. Therefore, heterobivalent probes targeting both PSMA and NTS
1
could improve the prostate cancer management. Herein, we report the development of a branched hybrid probe (
JMV 7489
) designed to target PSMA and/or NTS
1
bearing relevant pharmacophores and DOTA as the chelating agent. The new ligand was synthesized with a hybrid approach, which includes both syntheses in batch and in the solid phase. Saturation binding experiments were next performed on HT-29 and PC3-PIP cells to derive
K
d
and
B
max
values. On the PC3-PIP cells, [
68
Ga]Ga-
JMV 7489
displayed good affinity towards PSMA (
K
d
= 53 ± 17 nM;
B
max
= 1393 ± 29 fmol/10
6
cells) in the same range as the corresponding reference monomer. A lower affinity value towards NTS
1
was depicted (
K
d
= 157 ± 71 nM;
B
max
= 241 ± 42 fmol/10
6
cells on PC3-PIP cells;
K
d
= 246 ± 1 nM;
B
max
= 151 ± 44 fmol/10
6
cells on HT-29 cells) and, surprisingly, it was also the case for the corresponding monomer [
68
Ga]Ga-
JMV 7089
. These results indicate that the DOTA macrocycle and the linker are critical elements to design heterobivalent probes targeting PSMA and NTS
1
with high affinity towards NTS
1
.
Linker and chelating agents strongly influence the binding affinity of the NTS
1
-PSMA heterobivalent probe towards NTS
1
. Comparable affinities between mono- and heterobivalent ligands towards PSMA were observed. |
|---|---|
| Bibliografia: | https://doi.org/10.1039/d4md00491d Electronic supplementary information (ESI) available. See DOI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 2632-8682 2632-8682 |
| DOI: | 10.1039/d4md00491d |