177Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model

Abstract

Background177Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of 177Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications.Results177Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq 177Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels.ConclusionsThe 177Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0204-9) contains supplementary material, which is available to authorized users.

Advantages and Limits of Targeted Radionuclide Therapy with Somatostatin Antagonists

“…Two hundred micrograms are considered the upper limit for the agonist; however, there are indications that 200 mg might represent a starting dose for the antagonists. We understand the limitation of allometric scaling from mice to humans (5) and therefore agree with the authors that the benefit (safety and efficacy) of injecting larger amounts of antagonist peptide still needs to be investigated clinically. Animal experiments have been crucial in discovering the potential benefit of higher peptide mass, and these results should not be neglected because of hypotheses that have not been demonstrated.…”

“…Also, in the human pilot study with 177 Lu-DOTA-JR11 (;150 mg peptide mass), the images recorded at 24 and 72 h showed low uptake in the pancreas and stomach, and the radiation dose to the pancreas and stomach wall were about 15 times lower than that to the kidneys (2). The biodistribution seems to be species-dependent: for example, differently from humans, pigs displayed a high uptake of 177 Lu-DOTA-JR11 in the osteogenic bone, but the spleen was not visible (5).…”

The theranostic promise for Neuroendocrine Tumors in the late 2010s - Where do we stand, where do we go?

“…Notably, up to 4.4 times higher tumor doses per injected activity were detected with OPS201 (1.8 ± 0.7 Gy/MBq vs. [ 177 Lu]-DOTATATE, 0.36 ± 0.07 Gy/MBq) 16, 47. Biodistribution in pigs also demonstrated encouraging results, which forecasts radiation exposure in humans in an acceptable range 48. A recently published abstract reported on 19 patients who underwent [ 68 Ga]-OPS202 imaging and subsequent [ 177 Lu]-OPS201 therapy (with 7/19 receiving two cycles): 1 patient achieved a complete response, 32% partial response and 47% remained stable.…”

Dosimetry and Toxicity Studies of the Novel Sulfonamide Derivative of Sulforhodamine 101([18F]SRF101) at a Preclinical Level

“…In addition, sources of errors due to the allometric approach (relative to mass scaling) can be introduced because scaling most likely decreases the values of time-integrated activity curves, and consequently, the absorbed doses may decrease, as found by Beykan et al [30]. Moreover, Kranz et al [28] concluded that the extrapolation of preclinical data obtained from studies in small animals, either by organ harvesting or PET images, would result in an underestimation of the human effective dose due to limitations in allometric scaling and species-specific target expression; however, the current data provide a reasonable basis for evaluating human dosimetry, which can be better-established in human subjects.…”