In vivo localization of delta opioid receptors on human small cell lung cancer xenografts in SCID mice using an indium-111 labeled DO3A conjugate of naltrindole

Abstract

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Objectives: The delta opioid receptor is over-expressed in small cell lung cancers (SCLC) with respect to normal lung. Imaging radioligands for peripheral delta opioid receptors could be valuable tools for diagnostic and basic science studies of SCLC. Our goals were to determine if a delta selective indium-labeled DO3A conjugate of naltrindole (NTI) could be used with human H69 SCLC xenografts in SCID mice to provide a useful radioligand / animal model system. Methods: We prepared an indium (III) / indium-111 labeled DO3A conjugate of NTI having a n-hexyl linker between the pendant chelator and the indole nitrogen of NTI. Cold complex was prepared in 7 steps from NTI, and gave N1-(In(III)-DO3A-hexyl)NTI in 14% overall yield. Radiolabeled complex was prepared in 65% yield by treatment with indium-111 chloride in acetate buffer at 100 degrees and HPLC purification. Receptor binding was assessed for cold complex by in vitro assays in rodent brain tissues, and for indium-111 labeled complex by in vivo studies in female SCID mice bearing H69 flank xenografts. Results: In vitro, indium (III) complex showed very high affinity for delta sites (Ki = 0.11 ± 0.01 nM) and >100-fold selectivity over mu (Ki = 34.4 ± 1.4 nM) and kappa (Ki = 14.4 ± 1.0 nM) binding. In vivo, the indium-111 labeled complex showed high uptake and retention in tumors (4.0 %ID/g, 1 h; 9.7 %ID/g, 48 h) and GI tract (15-20 %ID/g; 1 - 48 h). Muscle cleared over this period as a single exponential (r2 1.0) from 0.44 %ID/g to 0.04 %ID/g. Consequently, tumor to muscle ratios at 48 h were >200 to 1. NTI (5 umol/kg) pretreatment blocked uptake at 4 h in tumor (77%) and gut (95%). At 24 h, only non-metabolized radioligand was detected in urine, and in tumor (68% extraction efficiency). Conclusions: N1-([111In]-DO3A-hexyl)NTI exhibits high affinity and selectivity for delta opioid receptors in vitro, selectively labels delta opioid receptors in SCLC xenografts and the GI tract of SCID mice in vivo, and warrants further investigation as a SPECT ligand.

Research Support (if any): NCI P50 CA 103130