Velikyan I, Rosenström U, Bulenga TN, Eriksson O, Antoni G
Pharmaceuticals (Basel, Switzerland) 9 (2) - [2016-06-06; online 2016-06-06]
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. 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. 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. 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.