DOTA-zoledronate a novel bone seeking compound for Ga-68 PET diagnosis and Lu-177 endoradiotherapy of bone metastases: from preclinical to first human results

DOTA based bisphosphonates showed first promising results in patients suffering from bone metastases. When labeled with generator derived Ga-68 it enables high qualitative skeletal PET-scans for hospitals or even small nuclear medical facilities without a cyclotron infrastructure. Furthermore, DOTA based bisphosphonates are able to be used as therapeutic agents for the treatment of painful bone metastases, when labelled with low energy β-emitter Lu-177. Zoledronic acid is currently the most potent bisphosphonate in clinical use. Here we report the development of the novel DOTA zoledronic acid derivative suitable for Ga-68 PET Diagnosis and Lu-177 radiotherapy and its first in-men application. The novel DOTA-Zoledronate (DOTAM^ZOL) was successfully synthesized and labelled with Ga-68 and Lu-177 and evaluated in in vitro and in vivo studies in Wistar rats. The Ga-68 labelled analogous) Ga-68)DOTAM^ZOL was further used to perform a first in-men study in a male prostate cancer patient suffering from bone metastases. The SUV_max values in skeletal lesions and soft tissues like the liver, kidneys and salivary glands were compared to a previously done (Ga-68)HBED-PSMA scan. First applications of (Lu-177) DOTAM^ZOL in 10 patients suffering from bone metastases of different origin were performed with subsequent whole body scintigraphies at different time points after injection. The novel theranostic bisphosphonate DOTA-Zolendronate showed excellent radiolabeling yields with Ga-68 and Lu-177 and can be easily implemented in routine clinical use. (Ga-68)DOTAM^ZOL and) Lu-177)DOTAM^ZOL showed a very similar distribution in the rat model with a total skeletal retention of almost 50 %ID, which is very similar to those (F-18)NaF. The compound showed fast blood clearance and renal excretion pathway. First human PET results showed an excellent target-to-background ratio superior to radiolabelled PSMA in context of bone lesions. The SUV_max in bony lesions was obviously higher for DOTAM^ZOL (e.g. L2 vertebra SUV_max=68.9) compared to PSMA (e.g. L2 vertebra SUV_max=8.8). First applications of (Lu-177) DOTAM^ZOL in metastatic patients showed strong accumulation of the therapy compound 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 478 ng/mL to 88 ng/mL two month after he received a single treatment with 5.5 GBq (Lu-177) DOTAM^ZOL. The novel DOTA-Zoledronate DOTAM^ZOL showed promising results in preclinical studies and in first patient applications. The theranostic Ga-68/Lu-177 concept shows currently excellent results in the treatment of neuroendocrine tumors. The compound DOTAM^ZOL extends this concept for a promising bone metastases treatment. (author)