Process for the preparation of radiopharmaceuticals

Details Process for the preparation of radiopharmaceuticals Process for the preparation of radiopharmaceuticals

1997-10-28

2002-09-10

Jones, Dameron L. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C546S124000, C424S001110, C424S001650

Reexamination Certificate

active

06447747

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of radiotracers and radiopharmaceuticals, and more particularly to an improved process for preparing radiopharmaceuticals labeled with electrophillic halogens such as radioactive iodine. The present invention specifically relates to halogenodestannylation reactions, in particular iododestannylation reactions, in which the yield is significantly enhanced by the presence of a catalytically effective amount of a bromide, chloride or nitrite anion during the reaction.
BACKGROUND OF THE INVENTION
Radiotracers and radiopharmaceuticals are useful in the diagnosing, studying and monitoring of medical conditions and the uptake of pharmaceutical compositions. Some radiopharmaceuticals have therapeutic indications. Of particular interest are those pharmaceutical compositions that block access to or are taken up by the receptor binding agents for dopamine transporters/cocaine receptor binding sites.
Radiopharmaceuticals that bind to the dopamine transporter/cocaine receptor binding sites have a variety of potential uses. Because of the unique anatomical location of the dopamine transporter/cocaine receptor binding sites, a high affinity probe for imaging of these sites in vivo in the brain may be carried out using, for example, positron emission tomography (PET) or single photon emission computed tomography (SPECT). Thus, potential uses include imaging probes for dopamine transporter/cocaine binding sites, imaging probes for neurodegenerative disorders, monitoring means for drug therapies for cocaine abuse and monitoring means for drug therapies for neurodegenerative disorders such as Parkinson's disease.
The imaging probes for the dopamine transporter/cocaine receptor binding sites are useful for the purposes of (i) assaying cocaine receptors in chronic cocaine users and in individuals exposed to cocaine prenatally, (ii) assaying the receptor occupancy of potential cocaine therapeutics, and (iii) assaying cocaine receptors in individuals that abuse other drugs. Such imaging is also useful for monitoring the occupancy of the dopamine transporter by established and novel drugs that are targeted to and/or bind to these sites; these drugs include, but are not limited to, antidepressants (e.g., bupropion), attention deficit disorder/hyperactivity syndrome therapies (e.g., methylphenidate or pemoline), and dopamine uptake inhibitors useful for treating Parkinson's disease (e.g., benztropine, also termed cogentin).
Additionally, such imaging agents are useful for diagnosing or monitoring various central nervous system (CNS) disorders and neuropsychiatric disorders that involve dopamine transporters such as Parkinson's disease, a neurological disorder characterized by the degeneration of dopamine nerve terminals; Alzheimer's disease; schizophrenia and Tourette's syndrome. These imaging agents can be used to compare resultant image densities in normal and disease states and use the observed changes associated with these diseases as indicators diagnostic of diseased states. For example, in Parkinson's disease, there is a degeneration of dopaminergic nerve terminals in basal ganglia; the degeneration of these nerve terminals result in a loss of dopamine transporters in this region and this loss could be detected by imaging dopaminergic transporters. These imaging agents can also be employed to determine progression of the disease and/or prognosis as to various treatment regimes.
Finally, radiopharmaceuticals can be used to screen for drugs that would have a high affinity at serotonin transporters or dopamine transporters. Serotonin transporters are important in that they are a target for antidepressant drugs. Radio-labeled ligands can be used in screening studies to identify potentially new useful antidepressant drugs and to identify compounds that could be transported by or into various nerve terminals and be neurotoxic.
Therefore, stable, radiolabeled ligands, i.e., radio-labeled tracers and radiopharmaceuticals, suitable for visualizing and measuring changes of these sites in vivo in conjunction with functional imaging, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), are valuable tools for the diagnosis and treatment of neurodegenerative diseases associated with dopaminergic neurons as well as the monitoring of cocaine addiction treatments. Such functional imaging techniques provide information about the location, number, and size of specific neurological phenomena. Moreover, the ability to monitor changes of the dopamine (DA) transporter with optimal radioligands in the human brain may enable diagnosis and monitoring of the CNS consequences associated with cocaine abuse.
Radiolabelling of these cocaine derivatives and analogues, and other ligands that bind to the neuronal dopamine and serotonin reuptake transporters has been achieved by several methods. Preferred methods in the prior art have included radioiodination procedures by non-isotopic exchange on the bromo-analogue (nucleophilic non-isotopic iodo-for-bromo exchange) and iododestannylation of a trialkyltin or trialkylstannyl precursor. Of these methods, iododestannylation has been preferred as a means for preparation of aromatic radioiodinated tracers relatively rapidly with relatively high yield and specific activity.
Although good to high yields of radiolabeled pharmaceuticals have been reported in the literature, this has been for small scale batch preparation of approximately 1 to 5 patient doses per batch with a relatively low radioactivity, on the order of 10 mCi, associated with the radiolabel. However, we have discovered that when attempts are made to scale up production to at least 25 to 35 patient doses per batch, not only does the yield drop significantly, but side reactions become significant leading to the presence of undesired byproducts in the resultant product. Thus, the prior art process have lower yields that are produced at a greater cost and longer time due to the additional purification steps required.
Part of the problem with scale up to commercial levels may be associated with or attributed to the use of a radiolabel with higher activity. At small scale production, the radiolabeled pharmaceutical is used shortly after it is made. With larger scale production, a longer time elapses before the radiopharmaceutical is used, thus necessitating radiolabels with higher radioactivity levels on the order of 100 to 150 mCi or greater. However, it is well known in the art that the higher activity levels have a detrimental effect on chemical reactions involving the radiolabel, thus adversely impacting the yield and purity of the resultant product. This adverse effect of higher activity levels is referred to as radiolysis.
Those skilled in the art also believed that a particular problem is associated with the presence of chloride anions and other reactive anions in the iododestannylation process since they may compete with the iodide anion in the halogenodestannylation reaction, thus interfering with the iododestannylation reaction and producing undesired byproducts. As noted above, this effect may become more pronounced at higher activity levels.
Surprisingly, we have discovered that in the presence of a catalyst—particularly a small but catalytically effective amount of a bromide, chloride or nitrite anion—the yield of the iododestannylation chemical reaction significantly improved resulting in considerably purer radiopharmaceutical compositions. The improvement was especially significant when the reaction was conducted with a radiolabel having high amounts of radioactivity on the order of 100mCi to 600mCi, and even greater.
As used herein, the term catalyst refers to an agent, i.e. the bromide, chloride, or nitrite anion, also referred to as a catalytic anion, that brings about a modification, particularly an increase in the yield of the desired reaction product. The term catalytically effective amount refers to an amount sufficient to bring about the increase

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