Increased expression of neurotensin receptor 1 (NTR1) has been shown in a large number of tumor entities such as pancreatic or colon carcinoma. Hence, this receptor is a promising target for diagnostic imaging and radioligand therapy. Using the favorable biodistribution data of the NTR1-targeting agent In-3BP-227, we investigated the therapeutic effect of itsLu-labeled analog on the tumor growth of NTR1-positive HT29 colon carcinoma xenografts. 3BP-227 was labeled withLu. To assess its biodistribution properties, SPECT and CT scans of HT29-xenografted nude mice injected with Lu-3BP-227 were acquired, and ex vivo tissue activity was determined. To evaluate therapeutic efficacy, 2 groups of mice received the radiopharmaceutical in a median dose of either 165 MBq (129-232 MBq, = 10) or 110 MBq (82-116 MBq, = 10), whereas control mice were injected with vehicle ( = 10). Tumor sizes and body weights were monitored for up to 49 d. Renal function and histologic morphology were evaluated. Whole-body SPECT/CT images allowed clear tumor visualization with low background activity and high tumor-to-kidney and -liver ratios. Ex vivo biodistribution data confirmed high and persistent uptake ofLu-3BP-227 in HT29 tumors (19.0 ± 3.6 vs. 2.7 ± 1.6 percentage injected dose per gram at 3 and 69 h after injection, respectively). The application of Lu-3BP-227 resulted in a distinct delay of tumor growth. Median tumor doubling time for controls was 5.5 d (interquartile range [IQR], 2.8-7.0), compared with 17.5 d (IQR, 5.5-22.5 d) for the 110-MBq and 41.0 d (IQR, 27.5-55.0) for the 165-MBg group. Compared with controls, median relative tumor volume at day 23 after injection was reduced by 55% ( = 0.034) in the 110-MBq and by 88% ( < 0.01) in the 165-MBq group. Renal histology and clinical chemistry results did not differ between radiotherapy groups and controls, suggesting absence of therapy-induced acute renal damage. These data demonstrate that the novel NTR1-targeting theranostic agent 3BP-227 is an effective and promising candidate for radioligand therapy, with a favorable preliminary safety profile and high potential for clinical translation.

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Our findings show that the indirect targeting of the STN using coordinates based on radiological landmarks is more accurate than the direct targeting using anatomic visualization of the target structure. Regardless of the imaging procedure, electrophysiological mapping is required for optimal electrode placement, although in 20% of cases, the target determined by MRI falls out of the radius explored by electrophysiology.