Labelled ascorbic acid derivatives

Details Labelled ascorbic acid derivatives Labelled ascorbic acid derivatives

2002-09-16

2004-06-15

Jones, Dameron L. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S009100, C424S001850, C424S001810, C549S315000, C534S014000

Reexamination Certificate

active

06749832

ABSTRACT:

FIELD OF INVENTION AND BACKGROUND TO THE INVENTION
The present invention relates to a class of compounds useful in the diagnosis or radiotherapy of metastatic bone disease, pharmaceutical formulations containing them, their use in the diagnosis of disease and monitoring of disease progression and treatment, and methods for their preparation.
CURRENT BONE IMAGING AGENTS
Bone is a common site of metastatic disease with around 70-80% of breast and prostate cancers metastasising to bone. Lung, thyroid, kidney and bladder cancers can also metastasise to bone. Once tumour cells are implanted in the bone marrow they release biochemical mediators which activate osteoblasts. The osteoblastic response detected on a bone scan is a secondary response. Osteoblasts are bone-producing cells implicated in the pathology associated with metastatic bone disease. Activated osteoblasts produce large quantities of collagen that, in addition to its structural role, is important in osteoblast differentiation.
Diagnosis of metastatic bone disease may be achieved by one of four methods—radiography, CT scanning, radioisotope bone scan or MRI. The radioisotope bone scan has been the standard initial imaging method for the past 25 years. The usual tracer for bone scans is
99m
Tc-methylene diphosphonate (
99m
Tc-MDP).
99m
Tc-HMDP (hydroxy-methylenediphosphonate) and
99m
Tc-HEDP (1-hydroxyethyl-1,1-diphosphonate) may also be used. These agents have broadly similar characteristics. Around 550-750 MBq (15-20 mCi) is injected and high bone uptake (30-50% of the injected dose) occurs within 2 hours. Scans are typically carried out 3-4 hr post administration of agent, due to slow clearance from the blood and/or tissue. Whole body imaging (anterior/posterior) with an acquisition time of 20-30 min produces images of high quality, good resolution and high sensitivity/specificity.
99m
Tc-MDP is adsorbed onto the calcium of hydroxyapatite in bone. This process is influenced by the levels of osteoblastic activity and by skeletal vascularity. There is preferential uptake at sites of active bone formation, and the amount of accumulation is sensitive to the level of blood flow. The bone scan therefore reflects the metabolic reaction of bone to the disease process, regardless of whether the metabolic activity is neoplastic, traumatic or inflammatory in nature. Thus, the tracer accumulates at any site of elevated bone turnover and the scan is therefore very non-specific.
Osteoblastic metastases resulting in hot spots are detected regardless of size but a cold (photopenic) spot, caused as a result of osteolytic disease, has to reach a certain size to be detected.
The general advantages of the radioisotope scan are a large field of view, low cost, low morbidity, high sensitivity for detection of skeletal metastases, ease of performance on any patient and relatively low total body dose.
DISADVANTAGES AND PROBLEMS ASSOCIATED WITH CURRENT RADIOISOTOPE BONE IMAGING AGENTS
Tracer accumulation may occur at any skeletal site with an elevated rate of turnover and in this case does not provide functional or vascular information. As the bone scan has low specificity, the nature of an abnormality cannot be determined from the scan, hence benign and malignant lesions often cannot be distinguished. The technique is also anatomically imprecise. Binding to bone can still occur after tumour cells are dead as collagen is still produced. Consequently there is no distinction between bone healing and tumour progression, with the result that it is difficult to monitor effects of treatment. An increase in the uptake of
99m
Tc-MDP due to bone healing can be seen up to 6 months after treatment and is known as the flare response.
There is no net production of collagen in osteolytic disease, hence false negatives occur—some or all lesions are missed. Such negative scans need to be re-evaluated with clinical and lab findings. If these are non-conclusive then radiography is used, if this is still non-conclusive then bone biopsy or MRI are used.
The low specificity of
99m
Tc-MDP means the nature of the abnormality e.g. benign vs malignant lesion cannot be detected. In a patient with known primary tumours, multiple hot spots in the bone scan indicate metastases. However 50% of these hot spots could be other non-metastatic lesions. Therefore a lack of specificity observed with
99m
Tc-MDP means that positive scans often have to be accompanied by radiographic correlation (a positive radiograph confirms the presence of metastases as the bone scan is more sensitive, but a negative radiograph does not rule them out).
MRI is sometimes chosen, mainly due to its ability to demonstrate abnormalities in bone marrow. However, MRI often cannot distinguish between changes that are due to treatment, fracture and tumour and is less well suited to scanning long bones.
Despite the problems associated with the current radioisotope bone imaging agents, their unique features make them the first choice for screening for metastases in a symptomatic patients. However, a negative scan should always be re-evaluated with clinical and laboratory findings due to the possibility of false negatives. Furthermore, the possibility of a non-metastatic cause of an abnormal scan always needs to be considered. Non-conclusive findings generally lead to supplementary examination with radiography. If diagnosis is still unclear, bone biopsy or MRI will be performed.
There is therefore a need for a diagnostic imaging agent which has specificity for metastatic bone lesions (as opposed to other lesion types), and which can give clinically useful information in a single imaging protocol, without the need for additional testing.
Skeletal metastases may respond to chemotherapy or hormone therapy used to treat the primary tumour. They may also respond to radiation or to agents designed to block bone resorption such as the new class of bisphosphonate (BP) drugs. Bisphosphonates have potent inhibitory effects on bone resorption and are the treatment of choice for hypercalcaemia of malignancy. Treatment can lead to a reduction in the number and rate of skeletal complications in multiple myeloma and advanced breast cancer and can delay the onset of progressive disease in bone following palliative chemotherapy in breast cancer and myeloma. BPs also relieve metastatic bone pain in around 50% of patients but this requires intravenous injection as BPs are not potent enough and not tolerated well when taken orally. Response to treatment can be measured by biochemical markers e.g. excretion of collagen cross-links. Radioisotopes are also used in the treatment of bone metastases [Ben-Josef & Porter, Ann Med. 29, 31-35, (1997); Lewington, Phys Med Biol. 41, 2027-2042 (1996)].
89
Sr has been successfully used in pain palliation. Other bone-seeking isotopes include
32
P (side effect of myelotoxicity),
153
Sm (complexed with EDTMP) and
186
Re (complexed with HEDP).
14
C and
3
H-labelled ascorbic acid derivatives are known. Yamamoto et al [Appl. Radiat. Isot. 43, 633-639 (1992)] have described the preparation of 6-deoxy-6-[
18
F]fluoro-L-ascorbic acid (
18
F-DFA), i.e. an ascorbic acid derivative labelled with the positron emitting isotope [
18
F] via nucleophilic displacement of a cyclic sulfate with fluoride ion. The biodistribution of this compound has been studied in rats and fibrosarcoma-bearing mice. Yamamoto et al [Radioisotopes, 44, 93-98 (1995)] have also studied the biodistribution of
18
F-DFA in Wistar normal rats, ODS rats unable to synthesise ascorbic acid, and Wistar male rats implanted with RG-G6 glioma intracerebrally, and [Nucl. Med. Biol., 23, 479-486 (1996)] the in vivo uptake and distribution of
18
F-DFA in rat brains following postischemic reperfusion.
The bone uptake reported for
18
F-DFA is very low and there is no suggestion that labelled ascorbic acid derivatives could be useful for either bone imaging in general, or metastatic bone disease imaging in particular. In addition,
18
F has a half life of 1.8 hours, and is t

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