DOTAZOL as novel bone seeking compound for Ga-68 PET diagnosis and Lu-177 endoradiotherapy of bone metastases: From preclinical to first human results

Objectives DOTA based bisphosphonates (BP) showed first promising results in patients suffering from bone metastases. Labeled with Ga-68 they enable high-qualitaty skeletal PET-scans for hospitals or even small nuclear medical facilities without cyclotron. Furthermore, DOTA based BP can be used for the treatment of painful bone metastases when labeled with low energy β-emitter Lu-177. Zoledronic acid is currently the most potent BP in clinical use. Here we report the development of a novel DOTA Zoledronic acid derivative DOTAZOL (MM.MZ) suitable for Ga-68 PET diagnosis and Lu-177 radiotherapy and its first human application.

Methods DOTAZOL was labeled with Ga-68 and Lu-177 and evaluated in in vitro and in vivo studies. Ga-68-DOTAZOL was used to perform a first in-men study in a male prostate cancer patient suffering from bone metastases. SUVmax values in skeletal lesions and soft tissues like liver, kidneys and salivary glands were compared to a previously done Ga-68-HBED-PSMA scan. First applications of Lu-177-DOTAZOL in 10 patients suffering from bone metastases of different origin were performed with subsequent whole body scintigraphies at different time points p.i..

Results The novel theranostic BP DOTAZOL showed excellent radiochemical yields with Ga-68 and Lu-177 and can be easily implemented in routine clinical use. Ga-68-DOTAZOL and Lu-177-DOTAZOL showed similar distribution in the rat model with a total skeletal retention of almost 50 %ID which is comparable to 18-F-NaF and fast renal clearance. First human PET results showed an excellent target-to-background-ratio superior to radiolabeled PSMA in context of bone lesions. SUVmax in bone lesions was higher for DOTAZOL (e.g. L2 vertebra SUVmax=68.9) compared to PSMA (e.g. L2 vertebra SUVmax=8.8). First applications of Lu-177-DOTAZOL in metastatic patients showed high accumulation in bone lesions determined by planar scintigraphic images and SPECT/CT. In an individual application the PSA value of a prostate cancer patient decreased from 1217.8 ng/mL to 88 ng/mL two month after a single treatment with 5.5 GBq Lu-177-DOTAZOL.

Conclusions The novel DOTA-BP DOTAZOL (MM.MZ) showed promising results in preclinical studies and first patient applications. The theranostic Ga-68/Lu-177 concept currently shows excellent results in the treatment of neuroendocrine tumors. DOTAZOL extends this concept for a promising bone metastases treatment.