New Theranostic Radionuclides for Metastatic Bone Disease

Abstract

Introduction: The availability of imaging and therapeutic radionuclides directed against same molecular targets has actualized theranostics and possibility of personalized treatment in nuclear medicine. For personalized medicine with maximum effect of therapy at target with therapeutic radionuclide, diagnostic radionuclide is required to select appropriate patient that can benefit from therapy and tailor the therapeutic doses with possible prospective dosimetric analysis for therapeutic radionuclides. Hence necessitates biodistribution and dosimetric analysis of diagnostic as well as therapeutic radionuclide. In this study, the biodistribution and dosimetric analysis of [⁶⁸Ga]Ga-DOTA^ZOL and [¹⁷⁷Lu]Lu-DOTA^ZOL (specific bone seeking radiopharmaceuticals) in patients with skeletal metastatic disease and [⁴⁴Sc]Sc-PSMA-617 (nonspecific bone seeking radiopharmaceutical) in mCRPC patients has been assessed to establish their feasible theranostic use. Further, possibility of calculation of normal organ absorbed doses for [¹⁷⁷]Lu-DOTA^ZOL and [¹⁷⁷]Lu-PSMA-617 with [⁶⁸Ga]Ga-DOTA^ZOL and [⁴⁴Sc]Sc-PSMA-617 respectively has been explored. Materials and Methods: A total of fourteen patients were enrolled for biodistribution and dosimetric analysis; five for [⁶⁸Ga]Ga-DOTA^ZOL (mean age: 72 y), four for [¹⁷⁷]Lu-DOTA^ZOL (mean age: 69.3 y)and 05 patients for [⁴⁴Sc]Sc-PSMA-617 (mean age: 69 y). PET/CT scintigraphy (dynamic + static skull to mid-thigh) along with blood and urine samples for [⁶⁸Ga]Ga-DOTA^ZOL and [⁴⁴Sc]Sc-PSMA-617 and gamma camera planar whole body scintigraphy with blood samples collection for [¹⁷⁷]Lu-DOTA^ZOL at multiple time points was used to determine the kinetics of respective radiopharmaceuticals. For quantitative analysis of PET/CT studies for [⁶⁸Ga]Ga-DOTA^ZOL and [⁴⁴Sc]Sc-PSMA-617 interview fusion software (MEDISO Medical Imaging Systems, Budapest, Hungary) was used. Percent of injected activities in source organs, blood and urine samples was used to perform kinetic analysis, residence time (MBq-h/MBq) and organ absorbed dose determination using OLINDA/EXM version 2.0 software (Hermes Medical Solutions, Stockholm, Sweden). To determine residence times and organ absorbed doses with OLINDA/EXM version 2.0 software (Hermes Medical Solutions, Stockholm, Sweden) for [¹⁷⁷]Lu-DOTA^ZOL, percent of injected activity in source organs was determined using EANM dosimetry guidelines and methodology explained in MIRD pamphlet no 16. For prospective dosimetric analysis the pharmacokinetic analysis of [⁶⁸Ga]Ga-DOTA^ZOL and [⁴⁴Sc]Sc-PSMA-617 was mathematically extrapolated for [¹⁷⁷]Lu-DOTA^ZOL and [¹⁷⁷]Lu-PSMA-617 respectively. Results: Biodistribution and dosimetric analysis of [⁶⁸Ga]Ga-DOTA^ZOL revealed urinary bladder as critical organ with highest absorbed dose (0.338 mSv/ MBq) and skeleton as target organ. Besides high urinary bladder and kidney absorbed doses, mean effective dose was found similar to [¹⁸F]NaF. Its biodistribution was also found comparable with [¹⁸F]NaF, [⁹⁹mTc]Tc-MDP and [⁶⁸Ga]Ga-PSMA-617. Biodistribution and dosimetric analysis of [¹⁷⁷]Lu-DOTA^ZOL showed early, high uptake in kidneys with fast clearance and gradual rise of activity in skeleton. Mean organ absorbed doses were highest in osteogenic cells (3.33 MSv/ MBq) followed by kidneys and red marrow. Maximum permissible activity was limited due to bone marrow toxicity. Prospective dosimetry with [⁶⁸Ga]Ga-DOTA^ZOL resulted in lower organ absorbed doses and lower therapeutic doses for [¹⁷⁷]Lu-DOTA^ZOL. Biodistribution of [⁴⁴Sc]Sc-PSMA-617 was found similar to [⁶⁸Ga]Ga-PSMA but with higher organ absorbed doses and lower effective dose. Kidneys with highest radiation absorbed dose of 0.319 mSv/ MBq were the critical organs, followed by urinary bladder wall and rest of organs. Prospective dosimetric analysis of [¹⁷⁷]Lu-PSMA-617 from extrapolated pharmacokinetics of [⁴⁴Sc]Sc-PSMA-617 revealed highest absorbed dose in the kidneys (0.44 mSv/MBq) followed by the salivary glands (0.23 mSv/MBq). The maximum permissible activity was highly variable among patients; limited by whole body absorbed dose (one patient), marrow absorbed dose (one patient) and kidney absorbed dose (three patients). Conclusions: [⁶⁸Ga]Ga-DOTA^ZOL and [¹⁷⁷]Lu-DOTA^ZOL can be employed for theranostics in patients with skeletal metastatic disease. [⁶⁸Ga]Ga-DOTA^ZOL needs to be used with diuretics to reduce absorbed doses to urinary bladder and kidneys. Moreover [⁶⁸Ga]Ga-DOTA^ZOL is not appropriate for prospective dosimetric analysis of [¹⁷⁷]Lu-DOTA^ZOL. The longer lived [⁴⁴Sc]Sc-PSMA-617 has been found an important theranostic radionuclide for diagnosis, follow up and probable pre-therapeutic personalized dosimetric analysis for [¹⁷⁷]Lu-PSMA-617 in mCRPC patients.