Preparation and preclinical evaluation of 68Ga-labeled alendronate analogs for diagnosis of bone metastases†

Abstract

Bone is one of the most common target organs for distant metastases of solid tumors, which imposes a heavy burden on society. Early diagnosis of bone metastases is of great significance and positron emission tomography (PET) imaging plays an important role in the diagnosis of bone metastases. PET tracers applied for diagnosing bone metastases are constantly being updated, but they all have certain limitations like a relatively low bone/kidney ratio or no capacity to label therapeutic radionuclides. Alendronate, a representative bisphosphonate (BP), has been usually considered the standard clinical treatment for bone related diseases. In this study, alendronate was strategically modified with different linkers in an attempt to improve target/non-target ratios and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was used as the chelator. Finally, three ⁶⁸Ga-labeled tracers were successfully developed. The results showed that [⁶⁸Ga]Ga-AABP1/2/3 all exhibited high radiochemical purity, biosafety, and excellent stability. In the biodistribution study of normal BALB/c mice, [⁶⁸Ga]Ga-AABP3, when modified with phenylalanine and β-alanine as the linker, showed the highest bone/non-bone ratio at 1.5 h. In micro-PET/CT imaging of normal BALB/c mice, [⁶⁸Ga]Ga-AABP3 showed the highest SUV_max value at the bones (2.24 ± 0.16 at 1.5 h). In micro-PET/CT imaging of the mouse model of bone metastases, compared with [⁶⁸Ga]Ga-AABP1 and [⁶⁸Ga]Ga-AABP2, the SUV_max in the foci after injection of [⁶⁸Ga]Ga-AABP3 was the highest (2.64 ± 0.08 at 0.5 h and 2.67 ± 0.10 at 1.5 h), significantly higher than that of the contralateral normal bone. Besides, [⁶⁸Ga]Ga-AABP3 showed the highest tumor/non-tumor ratio at 1.5 h. The results suggest that [⁶⁸Ga]Ga-AABP3 has the potential for diagnosis of bone metastases. Furthermore, AABP3 with the chelator DOTA could also be labeled with ¹⁷⁷Lu or ²²⁵Ac, providing possibility for further application in radioligand therapy.