RT Journal Article SR Electronic T1 68Ga-DOTA-NT-20.3 Neurotensin receptor 1 positron emission tomography imaging as a surrogate for neuroendocrine differentiation of prostate cancer JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP jnumed.121.263132 DO 10.2967/jnumed.121.263132 A1 Wen Yu Wu A1 Fei Yu A1 Peng Jun Zhang A1 Ting Bu A1 Jing Jing Fu A1 Shu Yue Ai A1 Qin Qin You A1 Liang Shi A1 Guo Qiang Shao A1 Feng Wang A1 Marina Hodolic A1 Hong Qian Guo YR 2022 UL http://jnm.snmjournals.org/content/early/2022/02/17/jnumed.121.263132.abstract AB PSMA-negative neuroendocrine prostate cancer (NEPC) is likely to be a lethal subtype of prostate cancer (PCa) with limited clinical diagnostic and therapeutic options. High expression of neurotensin receptor subtype 1 (NTR1) associated with neuroendocrine differentiation of PCa, which makes NTR1 a potential target for NEPC. In this study, NTR1-targeted tracer 68Ga-DOTA-NT-20.3 was synthesized and evaluated by determining its affinity to androgen-dependent (LNCap) and androgen-independent (PC3) xenografts. Methods: 68Ga-DOTA-NT-20.3 was labeled with an automated iQS-theranostics synthesizer module and its stability, labeling yield, and radiochemical purity were analyzed by radio-HPLC. Receptor binding affinity was evaluated in NTR1-positive PC3 cells by competitive binding assay. The biodistribution of 68Ga-DOTA-NT-20.3 in vivo was evaluated in PC3 and LNCap xenografts by micro-PET imaging. NTR1 expression was identified by immunohistochemistry and immunofluorescence. Results: 68Ga-DOTA-NT-20.3 was synthesized successfully with a yield rate of 88.07 ± 1.26 %, radiochemical purity ≥ 99% and favorable stability. The NTR1 affinity (IC50) for 68Ga-DOTA-NT-20.3 was 7.59 ± 0.41 nM. Micro-PET/CT in PC3 xenografts showed high contrast images with intense tumor uptake, which revealed specific NTR1 expression. The tumor showed significant radioactivity (4.95 ± 0.67 percentage of injected dose per gram of tissue [%ID/g]) at 1h, which fell to 1.95 ± 0.17 %ID/g (P < 0.01, t = 8.72) after specific blockage by neurotensin. LNCap xenografts had no significant accumulation (0.81 ± 0.06 %ID/g) of 68Ga-DOTA-NT-20.3 at 1 h. In contrast, 68Ga-PSMA-11 was mainly concentrated in LNCap xenografts (8.60 ± 2.11 %ID/g), with no significant uptake in PC3 tumors (0.53 ± 0.05 %ID/g), consistent with the in vitro immunohistochemistry findings. Biodistribution showed rapid clearance from the blood and main organs (brain, heart, lung, liver, muscle, bone) with significantly high tumor/liver (4.41 ± 0.73) and tumor/muscle ratios (12.34 ± 1.32) at 60 min post-injection. Conclusion: 68Ga-DOTA-NT-20.3 can be efficiently prepared with a high yield and radiochemical purity. Its favorable biodistribution and prominent NTR1 affinity make 68Ga-DOTA-NT-20.3 a potential radiopharmaceutical for the detection of PSMA-negative PCa and identification of neuroendocrine differentiation.