RESUMO
OBJECTIVES: Fibrosis is involved in many chronic diseases. It affects the functionality of vital organs, such as liver, lung, heart and kidney. Two novel imaging agents for positron emission tomography (PET) imaging of fibrosis have previously pre-clinically demonstrated promising target binding and organ distribution characteristics. However, the relevant disease monitoring in the clinical setup would require multiple repetitive examinations per year. Thus, it is of paramount importance to investigate the absorbed doses and total effective doses and thus, the potential maximum number of examinations per year. METHODS: Two cyclic peptide (c[CPGRVMHGLHLGDDEGPC]) analogues coupled via an ethylene glycol linker (EG2) to either 2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid (NO2A-Col) or 4-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (NODAGA-Col) were labelled with (68)Ga. The resulting agents, [(68)Ga]Ga-NO2A-Col and [(68)Ga]Ga-NODAGA-Col, were administered in the tail vein of male and female Sprague-Dawley rats (N = 24). An ex vivo organ distribution study was performed at the 5-, 10-, 20-, 40-, 60- and 120-min time points. The resulting data were extrapolated for the estimation of human organ and total body absorbed and total effective doses using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1) assuming a similar organ distribution pattern between the species. Time-integrated radioactivity in each organ was calculated by trapezoidal integration followed by a single-exponential fit to the data points extrapolated to infinity. The resulting values were used for the residence time calculation. RESULTS: Ex vivo organ distribution data revealed fast blood clearance and washout from most of the organs. Although the highest organ absorbed dose was found for kidneys (0.1 mGy/MBq), this organ was not the dose-limiting one and would allow for the administration of over 1460 MBq per year for both [(68)Ga]Ga-NO2A-Col and [(68)Ga]Ga-NODAGA-Col. The total effective dose was the limiting parameter with 0.0155/0.0156 (female/male) mSv/MBq and 0.0164/0.0158 (female/male) mSv/MBq, respectively, for [(68)Ga]Ga-NO2A-Col and [(68)Ga]Ga-NODAGA-Col. This corresponded to the total amount of radioactivity that could be administered per year of 643 and 621 MBq before reaching the annual limit of 10 mSv. Thus, up to six examinations would be possible. The residence time and organ absorbed doses in liver and spleen were higher for [(68)Ga]Ga-NODAGA-Col as compared to [(68)Ga]Ga-NO2A-Col. CONCLUSION: The limiting parameter for the administered dose was the total effective dose that would allow for at least six examinations per year that might be sufficient for adequate disease monitoring in longitudinal studies and a routine clinical setup.
RESUMO
Quantitative PET imaging with [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 has potential use in diabetes and cancer. However, the radiation dose to the kidneys has been a concern for the possibility of repeated imaging studies in humans. Therefore, we investigated the dosimetry of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 based on the biodistribution data in rats, pigs, non-human primates (NHP) and a human.Organ distribution of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in rats (Male Lewis; n=12; 30, 60, and 80 min) was measured ex vivo. The dynamic uptake of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in the abdomen was assessed by PET/CT scanning of pigs (male; n = 4, 0-60 min), NHP (Female; cynomolgus; n=3; 0-90 min), and human (female; n=1; 0-40, 100, 120 min).The organ distribution data in each species were extrapolated to those of a human, assuming similar distribution between the species. Residence times were assessed by trapezoidal approximation of the kinetic data. Organ doses (mGy/MBq) and the whole body effective dose (mSv/MBq), was extrapolated by using the OLINDA/EXM 1.1 software. The extrapolated human whole body effective dose was 0.017 ± 0.004 (rats), 0.014 ± 0.004 (pigs), 0.017 ± 0.004 (NHP), and 0.016 (human) mSv/MBq. The absorbed dose to the kidneys was limiting:0.33 ± 0.06 (rats), 0.28±0.05 (pigs), 0.65 ± 0.11 (NHP), and 0.28 (human) mGy/MBq, which corresponded to the maximum yearly administered amounts of 455 (rat), 536 (pig), 231 (NHP), and 536 (human) MBq before reaching the yearly kidney limiting dose of 150 mGy. More than 200 MBq of [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 can be administered yearly in a human, allowing for repeated (2-4 times) scanning. This potentially enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma.
RESUMO
[(68)Ga]-DO3A-VS-Cys(40)-Exendin-4 has been shown to be a promising imaging candidate for targeting glucagon like peptide-1 receptor (GLP-1R). In the light of radiotheranostics and personalized medicine the (177)Lu-labelled analogue is of paramount interest. In this study we have investigated the organ distribution of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 in rat and calculated human dosimetry parameters in order to estimate the maximal acceptable administered radioactivity, and thus potential applicability of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 for internal radiotherapy of insulinomas. Nine male and nine female Lewis rats were injected with [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 for ex vivo organ distribution study at nine time points. The estimation of human organ/total body absorbed and total effective doses was performed using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1). Six more rats (male: n = 3; female: n = 3) were scanned by single photon emission tomography and computed tomography (SPECT-CT). The renal function and potential cell dysfunction were monitored by creatinine ISTAT and glucose levels. The fine uptake structure of kidney and pancreas was investigated by ex vivo autoradiography. Blood clearance and washout from most of the organs was fast. The kidney was the dose-limiting organ with absorbed dose of 5.88 and 6.04 mGy/MBq, respectively for female and male. Pancreatic beta cells demonstrated radioactivity accumulation. Renal function and beta cell function remained unaffected by radiation. The absorbed dose of [(177)Lu]-DO3A-VS-Cys(40)-Exendin-4 to kidneys may limit the clinical application of the agent. However, hypothetically, kidney protection and peptidase inhibition may allow reduction of kidney absorbed dose and amplification of tumour absorbed doses.