PT  - JOURNAL ARTICLE
AU  - Jia, Yinnong
AU  - Fan, Wei
AU  - ZHANG, WENTING
AU  - Brusnahan, Susan
AU  - Garrison, Jered
TI  - 177Lu-labeled NTR1-targeted peptide for cancer diagnosis and therapy: the effect of charge distribution on the receptor binding and kidney retention
DP  - 2016 May 01
TA  - Journal of Nuclear Medicine
PG  - 1375--1375
VI  - 57
IP  - supplement 2
4099  - http://jnm.snmjournals.org/content/57/supplement_2/1375.short
4100  - http://jnm.snmjournals.org/content/57/supplement_2/1375.full
SO  - J Nucl Med2016 May 01; 57
AB  - 1375Objectives Neurotensin receptor 1 (NTR1) has been shown to be overexpressed in pancreatic cancer (1), colon cancer (2) and breast cancer (3). We and others have explored the development of NTR1-targeted agents, based on the neurotensin (NT) peptide, for cancer diagnosis and therapy (4). A major obstacle for clinical translation of NT analogs for radiotherapeutic applications is the potential nephrotoxicity due to the high kidney retention. Studies have demonstrated the relationship between positively charged peptides and kidney uptake (5). In this work, we investigated the effect of charge distribution on the receptor binding and kidney retention.Methods To this end, we synthesized three peptides with linking groups consisting of Lysine (K) and D-Leucine (DL) inserted in the paradigm DOTA-X-NT. Specifically, we synthesized K2, K4 and K6 where X= K-DL-DL-DL-DL, DL-DL-K-DL-DL, and DL-DL-DL-DL-K, respectively. To evaluate the binding affinity to the NTR1, competitive binding, internalization and efflux studies were conducted on the 177Lu-radiolabeled K2, K4 and K6 using the NTR1-positive HT-29, human colon cancer cell line. The biodistribution studies at 1, 4 and 24 hours post-injection of 177Lu-radiolabeled K2, K4 and K6 (370 kBq, 10 µCi) were examined using CF-1 mice. The collected kidneys were processed for autoradiography.Results From the in vitro studies, the binding affinity was significantly different with the positional translation of the positively charged amino acid. The K6 showed the highest binding affinity (21.8 ± 1.2 nM) and highest amount of internalization (4.06% ± 0.20% of the total added amount). In vivo biodistribution studies demonstrated that the 177Lu-K4 (64.81±10.81%ID/g) and 177Lu-K6 (68.99±6.22%ID/g) accumulated lower than 177Lu-K2 (127.51±13.15%ID/g) in kidney at 1 hour post-injection. Autoradiography studies of the kidneys indicated that 177Lu-K4 distributed homogenously in the whole kidney. In contrast, the 177Lu-K2 and 177Lu-K6 were mostly distributed in the cortex of kidney.Conclusions We conclude that the distribution of the positively charged amino acid (Lys) influences the receptor binding and kidney retention profile of the NTR1-targeted peptide. The studies to reveal the underlying mechanism of the kidney retention is still ongoing. $$graphic_C12216AD-E7D8-4978-BDC0-795A66022013$$