NO2APBP a novel Ga-68 PET bone targeting agent: From synthesis to first human application

Objectives Radiolabelled bisphosphonates (BP) are commonly used in diagnosis and therapy of skeletal diseases. Recently, DOTA-conjugated BPs have known value for PET/CT imaging, when labelled with Ga-68. A new NO2A based BP is described, labelled with Ga-68 and evaluated in vitro and in vivo in an animal model, followed by a first application in metastatic bone cancer patients.

Methods The macrocyclic BP NO2APBP was first synthesized and labelled by cation exchanged post processed Ga-68. Radiochemical yields were determined by TLC and HPLC. Binding experiments on artificial bone material was performed on Hydroxyapatite (HAP). In vivo μPET and ex vivo biodistribution studies were carried out in healthy Wistar rats. The animals were sacrified 60 minutes p.i. For the human study, a patient was chosen with proofed metastatic bone lesions in previous bone scans by [F-18]NaF, [Tc-99m]MDP and CT. Lesions were count and SUVmax values were determined.

Results Ga-68 labelling of NO2APBP occurred fast and robust. RCY of ≥ 98% were obtained. Adsorption studies on HAP showed a very high binding for [Ga-68]NO2APBP (93.8±4.4%). In vivo µPET showed a fast renal clearance of the radio tracer and a good accumulation on the bone (SUVmax: 2-4). Ex vivo biodistribution studies showed no significant uptake in other organs, besides the kidneys and the bladder and the targeted bone (Femur: 4.3 ± 0.9% ID/g, n = 5). [Ga-68]NO2APBP PET in patients showed superior quality compared to [Tc-99m]MDP SPECT. No significant differences were perceived in the qualitative PET scans of [Ga-68]NO2APBP compared to [F-18]NaF.

Conclusions The compound is fast and easy to label and it could be a very efficient tool for hospitals without a cyclotron infrastructure and an advantaged alternative to Tc-99m-BPs. In first human applications [Ga-68]NO2APBP proved to have high SUVs in metastatic lesion and a strong correlation in the detection efficiency compared to [F-18]fluoride.

Research Support EU COST TD1004 Max Planck Graduate Center