Endocrine Abstracts

Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals.

The traditional design of bone volume seeking radiopharmaceuticals based on e.g. trivalent radionuclides is to form radiometal-bisphosphonate complexes, with the bisphosphonate moieties being directly involved in the coordination chemistry of the radiometal.

Here, we propose a new design, disconnecting the bisphosphonate moiety and the radiometal coordination moiety by introducing a separate, physiologically inert chelate for the radiometal.

Several DOTA- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one NO2A derivative, were synthesized and labelled with both 68Ga and n.c.a. 177Lu. Radiolabeling yields for 68Ga- and 177Lu-DOTA and NO2A bisphosphonate complexes was >98% within 15 min. Within a series of next-generation bisphosphonates, a zoledronate derivative appeared to be superior to any other compounds tested.

Ex vivo biodistribution experiments and dynamic in vivo SPECT/CT measurements were performed in healthy rat for 1 h time points. Data on %ID/g or SUV for femur, blood and soft tissue organs were analysed. All radiopharmaceuticals showed exclusively accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data in the femur ranged from 3.34 to 5.67 at 60 min after injection in rat.

In patients, 68Ga-bisphosphonate PET imaging is (at least) as good as with 18F-fluoride. Preliminary human data demonstrate high uptake with SUVs reaching 100 and even 200. The 177Lu-complexes of macrocyclic bisphosphonates might be become therapy options for skeletal metastases. Together with analogue 68Ga bisphosphonates for PET/CT diagnosis, the new design provides excellent examples of radio-theranostics.