Abstract
The novel compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-ZOL (DOTA-conjugated zoledronic acid) is a promising candidate for the diagnosis and therapy of bone metastasis. The combination of the published methodology for this bisphosphonate with pharmaceutical and regulatory requirements turned out to be unexpectedly challenging. The scope of this work is the presentation and discussion of problems encountered during this process. Briefly, the radiolabelling process and purification, as well as the quality control published, did not meet the expectations. The constant effort setting up an automated radiolabelling procedure resulted in (a) an enhanced manual method using coated glass reactors, (b) a combination of three different reliable radio thin-layer chromatography (TLC) methods instead of the published and (c) a preliminary radio high-pressure liquid chromatography (HPLC) method for identification of the compound. Additionally, an automated radiolabelling process was developed, but it requires further improvement, e.g., in terms of a reactor vessel or purification of the crude product. The published purification method was found to be unsuitable for clinical routine, and an intense screening did not lead to a satisfactory result; here, more research is necessary. To sum up, implementation of DOTA-ZOL was possible but revealed a lot of critical points, of which not all could be resolved completely yet.
Highlights
The bone is, more than other tissues, affected by the metastasis of solid tumours [1,2] and is a prevalent complication in cancers of breast (BCa), prostate (PCa) and lung (LCa) [3]
The first to implement the novel compound DOTA-ZOL into radiopharmaceutical routine production for intended patient the studies exhibited a peck of trouble
For a better explanation and understanding, the radiolabelling/synthesis and purification are divided of the first attempts for the implementation are presented, as well as all findings that are based in two paragraphs and discussed separately
Summary
The bone is, more than other tissues, affected by the metastasis of solid tumours [1,2] and is a prevalent complication in cancers of breast (BCa), prostate (PCa) and lung (LCa) [3]. Apart from this, approximately 90% of patients diagnosed with stage IV PCa present bone metastases when diagnosed [8]. These bone lesions can induce skeletal-related events (SREs) as further complications of the disease, which are experienced by a further 5.9% of the patients [6]. These SREs, like pathological fractures, nerve compression syndromes or hypercalcemia, reduce the quality of life of the patients [9,10,11] and contribute to a major part to the significantly increased mortality and morbidity [12,13,14]
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