Title:<i>In vivo</i> Evaluation of [<sup>225</sup>Ac]Ac-DOTA<sup>ZOL</sup> for α-Therapy of Bone Metastases
VOLUME: 11 ISSUE: 3
Author(s):Nina Pfannkuchen, Nicole Bausbacher, Stefanie Pektor, Matthias Miederer and Frank Rosch*
Affiliation:Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz, Department of Nuclear Medicine, University Medical Center, Mainz, Department of Nuclear Medicine, University Medical Center, Mainz, Department of Nuclear Medicine, University Medical Center, Mainz, Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz
Keywords:Bone metastases, bisphosphonates, zoledronic acid, 225Ac, theranostics, α-emitter, radiolabelling.
Abstract:Background: Conjugates of bisphosphonates with macrocyclic chelators possess high potential
in bone targeted radionuclide imaging and therapy. DOTAZOL, zoledronic acid conjugated to DOTA
(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), demonstrated promising results in vivo in
small animals as well as in first patient applications using 68Ga for diagnosis via PET and the lowenergy
β-emitter 177Lu for therapy of painful bone metastases. In consideration of the fact that targeted
α-therapy probably offers various advantages over the use of β--emitters, the 225Ac-labelled derivative
[225Ac]Ac-DOTAZOL was synthesized and evaluated in vivo. Here, we report on radiolabelling and biodistribution
of [225Ac]Ac-DOTAZOL in healthy Wistar rats.
Methods: DOTAZOL was labelled with 225Ac and injected without further purification into the tail vein
with activities of 404 ± 47 kBq per animal. Ex vivo biodistribution studies were performed in healthy
Wistar rats at 1 hour, 24 hours, 5 days and 10 days post injection. The accumulation of [225Ac]Ac-
DOTAZOL on healthy bone and soft tissue organs was determined in terms of SUV. The results were
compared to those of other radiolabelled bisphosphonates such as [68Ga]Ga-DOTAZOL and [177Lu]Lu-
DOTAZOL. A group of 7 animals was observed over a period of 3 month after application of 394 kBq ±
10 kBq of [225Ac]Ac-DOTAZOL for signs of toxicity. After 3 months, kidneys were microscopically
analysed for signs of chronic kidney damage.
Results: Radiolabelling of DOTAZOL with 225Ac at 98 °C provided radiochemical yields ≥98 % within
30 minutes. [225Ac]Ac-DOTAZOL showed high femur uptake (SUVfemur = 4.99 ± 0.97, 10 d p.i.), which
was comparable to that of other Me(III)-DOTAZOL derivatives. Ratios between bone uptake and blood
pool activity reached levels of 5, 940, 2181 and 2409 at 1 hour, 24 hours, 5 days and 10 days post injection.
During the observation period of the first two month no toxicity was observed clinically. Histopathology
of kidneys after 3 month revealed significant tubular damage in most of the animals.
Conclusion: [225Ac]Ac-DOTAZOL repeats the well-known pharmacology of DOTAZOL derivatives in
preclinical evaluations. It thus may be considered for translational application together with strategies to
reduce renal toxicity.
