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Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors.

ABSTRACT: Somatostatin receptor subtype 2 (SSTR2) has become an essential target for radionuclide therapy of neuroendocrine tumors (NETs). JR11 was introduced as a promising antagonist peptide to target SSTR2. However, due to its rapid blood clearance, a better pharmacokinetic profile is necessary for more effective treatment. Therefore, two JR11 analogs (8a and 8b), each carrying an albumin binding domain, were designed to prolong the blood residence time of JR11. Both compounds were labeled with lutetium-177 and evaluated via in vitro assays, followed by in vivo SPECT/CT imaging and ex vivo biodistribution studies. [¹⁷⁷Lu]Lu-8a and [¹⁷⁷Lu]Lu-8b were obtained with high radiochemical purity (>97%) and demonstrated excellent stability in PBS and mouse serum (>95%). [¹⁷⁷Lu]Lu-8a showed better affinity towards human albumin compared to [¹⁷⁷Lu]Lu-8b. Further, 8a and 8b exhibited binding affinities 30- and 48-fold lower, respectively, than that of the parent peptide JR11, along with high cell uptake and low internalization rate. SPECT/CT imaging verified high tumor accumulation for [¹⁷⁷Lu]Lu-8a and [¹⁷⁷Lu]Lu-JR11 at 4, 24, 48, and 72 h post-injection, but no tumor uptake was observed for [¹⁷⁷Lu]Lu-8b. Ex vivo biodistribution studies revealed high and increasing tumor uptake for [¹⁷⁷Lu]Lu-8a. However, its extended blood circulation led to an unfavorable biodistribution profile for radionuclide therapy.

SUBMITTER: Koustoulidou S

PROVIDER: S-EPMC9503898 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors.

Koustoulidou Sofia S Handula Maryana M de Ridder Corrina C Stuurman Debra D Beekman Savanne S de Jong Marion M Nonnekens Julie J Seimbille Yann Y

Pharmaceuticals (Basel, Switzerland) 20220916 9

Somatostatin receptor subtype 2 (SSTR2) has become an essential target for radionuclide therapy of neuroendocrine tumors (NETs). JR11 was introduced as a promising antagonist peptide to target SSTR2. However, due to its rapid blood clearance, a better pharmacokinetic profile is necessary for more effective treatment. Therefore, two JR11 analogs (8a and 8b), each carrying an albumin binding domain, were designed to prolong the blood residence time of JR11. Both compounds were labeled with lutetiu ...[more]

PMID: 36145375

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Project description:Purpose To evaluate the predictive value of 7-week apparent diffusion coefficient change from baseline (ADCratio7w) at whole-body diffusion-weighted MRI (WB-DWI MRI) after one peptide receptor radionuclide therapy (PRRT) cycle to predict outcome in patients with metastatic neuroendocrine tumor (mNET). Materials and Methods From April 2009 to May 2012, participants in a prospective clinical trial investigating yttrium 90-DOTA Phe1-Tyr3-octreotide (DOTATOC) treatment for mNET (EudraCT no. 2008-007965-22) underwent WB-DWI MRI and gallium 68 (68Ga)-DOTATOC PET/CT before and 7 weeks after one PRRT cycle. ADCratio7w response was compared with the 7-week Response Evaluation Criteria in Solid Tumors version 1.1 and 68Ga-DOTATOC PET/CT quantitative responses to predict overall survival (OS) and progression-free survival (PFS) with Cox regression analysis. Results Forty participants were analyzed (mean age, 60 years ± 11 [SD]; 21 men). Median PFS and OS were 10.5 months (range, 2-36 months) and 18 months (range, 3-81 months), respectively. Survival analysis showed significantly positive effects on PFS by age (hazard ratio [HR] = 0.96, P = .007), tumor grade (HR = 2.84, P = .006), Ki-67 index (HR = 1.05, P = .01), ADCratio7w of the least-responding lesion (ADCratio7w-least) (HR = 0.94, P < .001), and baseline mean standardized uptake values (SUVmean) (HR = 0.89, P = .02), with ADCratio7w-least and SUVmean remaining significant in multivariable analysis (P < .001, P = .02, respectively). There were significantly positive effects on OS by pretreatment lesion volume (HR = 1.004, P = .004), tumor grade (HR = 2.14, P = .04), Ki-67 index (HR = 1.05, P = .01), and ADCratio7w-least (HR = 0.97, P < .001), with pretreatment volume and ADCratio7w-least remaining significant at multivariable analysis (P = .005, P = .002, respectively). Conclusion The ADCratio7w after start of PRRT for mNET was an independent predictor of patient outcome. Keywords: MR-Diffusion-Weighted Imaging, Radionuclide Therapy, Whole-Body Imaging, Metastases, Tumor Response, Treatment Effects EudraCT no. 2008-007965-22 © RSNA, 2022.

Dataset Information

Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors.

Publications

Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors.

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