First-in-human study of a novel somatostatin receptor antagonist ⁶⁸Ga-NODAGA-LM3 for molecular imaging of paraganglioma patients

Objectives: This study aims to analyze the safety and biodistribution of the somatostatin receptor (SSTR) antagonist ⁶⁸Ga-NODAGA-LM3 (NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid, LM3 = [p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2]) in comparison with the SSTR agonist ⁶⁸Ga-DOTATOC and to assess the diagnostic utility of ⁶⁸Ga-NODAGA-LM3 PET/CT in paraganglioma patients.

Methods: From March 2017 to June 2018, ten paraganglioma patients (7 males, 3 females; age 35 - 66 y, mean age 48.4 ± 11.0 y) were recruited after written informed consent. All patients underwent whole-body PET/CT scans at 45-55 min after intravenous injection of ⁶⁸Ga-NODAGA-LM3 (mean activity = 285 MBq, radiochemical purity > 95%). ⁶⁸Ga-DOTATOC PET/CT had been performed before (n=6) and/or after (n=4) ⁶⁸Ga-NODAGA-LM3 PET/CT for a head-to-head comparison as well as contrast-enhanced CT and MRI. 7 of the 10 patients were studied also by ¹⁸F-FDG and/or ¹⁸F-DOPA PET/CT. PET/CT images were analyzed qualitatively (visually) and semi-quantitatively (SUVmean and SUVmax). Regions of interest were drawn manually over major organs. Tumor-to-background ratios (TBR) were calculated using volume of interest (VOI) based SUVmax for target lesions (TL) and SUVmean for reference tissues (RT), namely, liver, kidney, spleen, background (gluteus muscle), for the corresponding ⁶⁸Ga-NODAGA-LM3 and ⁶⁸Ga-DOTATOC studies. Results: ⁶⁸Ga-NODAGA-LM3 was well tolerated in all patients, no adverse effects were noticed. ⁶⁸Ga-NODAGA-LM3 PET/CT showed positive findings in 10/10 patients with SUVmax of 2.51-299.95 [mean ± SD, 53.78 ± 183.2. The comparative physiological uptake of ⁶⁸Ga-NODAGA-LM3 to ⁶⁸Ga-DOTATOC (SUVmean [mean ± SD], ⁶⁸Ga-NODAGA-LM3 : ⁶⁸Ga-DOTATOC) in the liver, spleen, kidneys, red marrow were 5.55 ± 1.57 vs. 9.73 ± 2.30 (P < 0.01), 20.47 ± 6.93 vs 31,14 ± 7.50, 12.88 ± 4.57 vs 10.28 ± 2.02 and 1.16 ± 0.36 vs 0.98 ± 0.49, respectively. Compared with ⁶⁸Ga-DOTATOC PET/CT, ⁶⁸Ga-NODAGA-LM3 PET/CT detected many more (243 : 177) lesions including (27 : 18) lymph nodes, (11 : 3) liver and (190 : 143) bone metastases. With normal tissue as background, LM3 associated TBR were TL-liver 15.7, TL-kidney 6.8, TL-spleen 5.4, TL-gluteus 156.5, AL (mean value of all lesions)-liver 8.9, LL (liver metastases)-liver 5.1, AL-kidney 3.8, AL-spleen 2.4, AL-gluteus 57.5, respectively. Conclusion: This first-in-human study demonstrates safety and very high diagnostic accuracy of the new SSTR antagonist ⁶⁸Ga-NODAGA-LM3 for imaging of SSTR positive paragangliomas. It provides a very favorable biodistribution and was superior to the SSTR agonist in detecting tumor lesions, especially in the liver (due to the distinctively higher TBR) and in the skeletal system. The results emphasize the great potential of the SSTR antagonist ⁶⁸Ga-NODAGA-LM3 for diagnosis and for guiding SSTR-targeted therapy (theranostics) of paraganglioma patients.