68Ga-DOTA-NT-20.3 Neurotensin Receptor 1 PET Imaging as a Surrogate for Neuroendocrine Differentiation of Prostate Cancer

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F22%3A73612594" target="_blank" >RIV/61989592:15110/22:73612594 - isvavai.cz</a>

Výsledek na webu

<a href="https://jnm.snmjournals.org/content/early/2022/02/17/jnumed.121.263132" target="_blank" >https://jnm.snmjournals.org/content/early/2022/02/17/jnumed.121.263132</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.2967/jnumed.121.263132" target="_blank" >10.2967/jnumed.121.263132</a>

Jazyk výsledku

angličtina

Název v původním jazyce

68Ga-DOTA-NT-20.3 Neurotensin Receptor 1 PET Imaging as a Surrogate for Neuroendocrine Differentiation of Prostate Cancer

Popis výsledku v původním jazyce

Prostate-specific membrane antigen (PSMA)–negative neuroendocrine prostate cancer (PCa) is a subtype of PCa likely to be lethal, with limited clinical diagnostic and therapeutic options. High expression of neurotensin receptor subtype 1 (NTR1) is associated with neuroendocrinedifferentiation of PCa, which makes NTR1 a potential target for neuroendocrine PCa. In this study, the NTR1-targeted tracer 68Ga-DOTA-NT-20.3 was synthesized, and its affinity to androgen-dependent (LNCap) and androgen-independent (PC3) xenografts was determined. Methods: 68Ga-DOTA-NT-20.3 was labeled using an automated synthesizer module, and its stability, labeling yield, and radiochemical purity were analyzed by radio–high-performance liquid chromatography. Receptor binding affinity was evaluated in NTR1-positive PC3 cells by a competitive binding assay. The biodistribution of 68Ga-DOTA-NT-20.3 in vivo was evaluated in PC3 and LNCap xenografts by small-animal PET imaging. NTR1 expression was identified by immunohistochemistry and immunofluorescence evaluation. Results: 68 Ga-DOTA-NT-20.3 was synthesized successfully, with a yield of 88.07% 61.26%, radiochemical purity of at least 99%, and favorable stability. The NTR1 affinity (half-maximal inhibitory concentration) for 68 Ga-DOTA-NT-20.3 was 7.59 6 0.41 nM. Small-animal PET/CT of PC3 xenograft animals showed high-contrast images with intense tumor uptake, which revealed specific NTR1 expression. The tumors showed significant radioactivity (4.95 6 0.67 percentage injected dose per gram of tissue [%ID/g]) at 1 h, which fell to 1.95 6 0.17 %ID/g (P , 0.01, t 5 8.72) after specific blockage by neurotensin. LNCap xeno-grafts had no significant accumulation (0.81 6 0.06 %ID/g) of 68 Ga-DOTA-NT-20.3 at 1 h. In contrast, 68 Ga-PSMA-11 was concentrated mainly in LNCap xenografts (8.60 6 2.11 %ID/g), with no significant uptake in PC3 tumors (0.53 6 0.05 %ID/g), consistent with the in vitro immunohistochemistry findings. Biodistribution evaluation showed rapid clearance from the blood and main organs (brain, heart, lung, liver, muscle, and bone), with significantly high tumor-to-liver (4.41 6 0.73) and tumor-to-muscle (12.34 6 1.32) ratios at 60 min after injec-tion. Conclusion: 68 Ga-DOTA-NT-20.3 can be efficiently prepared with a high yield and high radiochemical purity. Its favorable biodistribution and prominent NTR1 affinity make 68 Ga-DOTA-NT-20.3 a potential adiopharmaceutical for the detection of PSMA-negative PCa andidentification of neuroendocrine differentiation.

Název v anglickém jazyce

68Ga-DOTA-NT-20.3 Neurotensin Receptor 1 PET Imaging as a Surrogate for Neuroendocrine Differentiation of Prostate Cancer

Popis výsledku anglicky

Prostate-specific membrane antigen (PSMA)–negative neuroendocrine prostate cancer (PCa) is a subtype of PCa likely to be lethal, with limited clinical diagnostic and therapeutic options. High expression of neurotensin receptor subtype 1 (NTR1) is associated with neuroendocrinedifferentiation of PCa, which makes NTR1 a potential target for neuroendocrine PCa. In this study, the NTR1-targeted tracer 68Ga-DOTA-NT-20.3 was synthesized, and its affinity to androgen-dependent (LNCap) and androgen-independent (PC3) xenografts was determined. Methods: 68Ga-DOTA-NT-20.3 was labeled using an automated synthesizer module, and its stability, labeling yield, and radiochemical purity were analyzed by radio–high-performance liquid chromatography. Receptor binding affinity was evaluated in NTR1-positive PC3 cells by a competitive binding assay. The biodistribution of 68Ga-DOTA-NT-20.3 in vivo was evaluated in PC3 and LNCap xenografts by small-animal PET imaging. NTR1 expression was identified by immunohistochemistry and immunofluorescence evaluation. Results: 68 Ga-DOTA-NT-20.3 was synthesized successfully, with a yield of 88.07% 61.26%, radiochemical purity of at least 99%, and favorable stability. The NTR1 affinity (half-maximal inhibitory concentration) for 68 Ga-DOTA-NT-20.3 was 7.59 6 0.41 nM. Small-animal PET/CT of PC3 xenograft animals showed high-contrast images with intense tumor uptake, which revealed specific NTR1 expression. The tumors showed significant radioactivity (4.95 6 0.67 percentage injected dose per gram of tissue [%ID/g]) at 1 h, which fell to 1.95 6 0.17 %ID/g (P , 0.01, t 5 8.72) after specific blockage by neurotensin. LNCap xeno-grafts had no significant accumulation (0.81 6 0.06 %ID/g) of 68 Ga-DOTA-NT-20.3 at 1 h. In contrast, 68 Ga-PSMA-11 was concentrated mainly in LNCap xenografts (8.60 6 2.11 %ID/g), with no significant uptake in PC3 tumors (0.53 6 0.05 %ID/g), consistent with the in vitro immunohistochemistry findings. Biodistribution evaluation showed rapid clearance from the blood and main organs (brain, heart, lung, liver, muscle, and bone), with significantly high tumor-to-liver (4.41 6 0.73) and tumor-to-muscle (12.34 6 1.32) ratios at 60 min after injec-tion. Conclusion: 68 Ga-DOTA-NT-20.3 can be efficiently prepared with a high yield and high radiochemical purity. Its favorable biodistribution and prominent NTR1 affinity make 68 Ga-DOTA-NT-20.3 a potential adiopharmaceutical for the detection of PSMA-negative PCa andidentification of neuroendocrine differentiation.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30224 - Radiology, nuclear medicine and medical imaging

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING

ISSN

1619-7070

e-ISSN

1619-7089

Svazek periodika

63

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

7

Strana od-do

1394-1400

Kód UT WoS článku

000859967100016

EID výsledku v databázi Scopus

2-s2.0-85138530690