Development of new radiotracers for the in-vivo assessment of biological functions and drug interactions

Cel

A.BACKGROUND

In vivo imaging of biological function has become of fundamental importance, not only for clinical diagnostic purposes, but also for basic medical research, and during drug development. While radiological methods such as CT and MRI contribute excellent morphological information, these methods are in most respects too insensitive to allow for characterisation of molecular interactions such as receptor binding and enzymatic reactions in vivo. Here we rely on the accelerated developments in nuclear medicine, with the development of new radioactive probes allowing for the in vivo detection of compounds in the nano- and pico-molar concentration range.

The radiotracer principle based on the use of radionuclides and labelled substances (i.e. radiotracers) makes the study of human physiology and pathophysiology possible and constitutes the basis of nuclear medicine. After administration, radiotracers can accumulate in specific regions of the body depending on their properties. External measurement and quantification largely depend on the selective uptake of the radiotracer; for quantification of physiological parameters highly specific radiotracers are required. The development of specific tracers, labelled with gamma- or positron-emitting radionuclides, has considerably enhanced nuclear medicine methodology, since these radiotracers can simulate biologically active substances. Thus, biological functions can be localized and quantified.

Besides the increased potential for refined diagnostic procedures, there is also a growing demand from pharmaceutical industry to have available imaging methods which fit into the process of drug development. This includes not only the potential to use imaging methods for the assessment of drug distribution in man, but more so, to have available specific and validated tracers by which biological and biochemical function can be recorded in vivo in patients and healthy volunteers. By the use of such probes, the new drugs can be characterised and quantified with respect to exact function at target biological systems. A growing number of examples are showing that this type of in vivo characterisation of drug interaction can create a better basis for planning clinical trials and shorten the times for testing of new agents.

Physiological processes, such as transport and metabolism place strict requirements on molecular structure, whereas receptor binding radioligands are characterised by high affinity for the binding site. The development of metabolic, pharmacological and receptor-affinity radiotracers labelled with either photon- or positron-emitting radionuclides is, in consequence, a multi-disciplinary task and can be seen as the result of several research elements.

The elements in a strategy for the development of radiotracers and radioligands for nuclear medicine are:

(a)identification of suitable areas of interest in nuclear medicine (organs, systems, lesions, etc.);

(b)defining the required tracer molecules;

(c)development of labelling methods with a suited photon- or positron-emitting radionuclides;

(d)structure-activity related biochemical evaluation of potentially useful radiotracers;
(e)development of acceptable quality control procedures;

(f)studies of pharmacological and pharmacokinetic parameters in experimental animal models;

(g)pharmacokinetic studies with SPET- and PET-radiotracers in healthy volunteers and in patients in compliance with the local legal requirements and ethical permissions;

(h)the compounds and methods developed in the COST framework should be evaluated at European level.

Nuclear medicine diagnostic procedures are highly dependent on the availability, efficacy, quality and safety of labelled compounds. Functional imaging of human (patho-) physiology in particular will benefit most from the development of new radiotracers and radioligands and of methods ensuring radiopharmaceutical quality. This is of general concern and will be beneficial to about three thousand researchers and clinicians in nuclear medicine throughout Europe.

No other European programme [EUREKA, BIOMED, etc.) deals with the envisaged topic. COST seems the most suitable framework; its broad forum allows also non-EC-countries (Switzerland, Slovenia, Hungary, Russia, etc.) to take part. A second advantage is the bottom up approach which we consider very important in this field and finally the COST is ideally suited to help establish the needed network.

Positive interaction is foreseen with the proposed COST Action B15 (Integrating knowledge during drug development through modelling of kinetics and dynamics) since their goal is complementary and will need our developed radiotracer as one of their tools, and with the COST Action "Coordination Chemistry".

B. OBJECTIVES AND BENEFITS

Due to the multi-disciplinary nature of radiotracer development, a European multi-centre cooperation is needed. Depending on know-how and technical facilities, partners will perform in a complimentary way special tasks in the field of chemical, radiochemical and pre-clinical development as well as establishing quality standards for safe application of radiotracers.

The main objective of this Action is to promote cooperation in the development of radiotracers for biomedical applications (making use of diverse European resources for this purpose).

This comprises:

-the synthesis of precursor molecules suitable for labelling with ? or á+-emitting radionuclides;

-the labelling of these precursors with these radionuclides;

-the evaluation of the biological effectiveness in experimental animal models;

-performing clinical trials and evaluation of the benefit of the new radiopharmaceuticals;

-providing pharmaceutical standards of preparation for safe application of the radiotracers (quality assurance programme);

-collaboration between university and pharmaceutical industry with respect to the utilisation of nuclear medicine probes in drug development.

Clinical evaluation will be performed at SPET- and PET-centres on healthy volunteers and ultimately in appropriate patient sub-groups. The pooling of results obtained at different centres will be encouraged to establish optimal diagnostic protocols.

The concept behind the proposal is that all interested partners are part of a network, which creates the environment for:

-coordinating existing and new cooperations in the described areas of scientific activity;

-facilitating the exchange of information and ensuring that opportunities are created, seized and developed. Regular meetings and workshops would be held for the coordination of research and the fast dissemination of results to all interested parties;

-providing exchange opportunities for young scientists and rapid transfer of methodology among groups/laboratories.

C.SCIENTIFIC PROGRAMME

The scientific programme will focus on a few important and challenging areas:

1.Radioligands for brain receptors

Neuropsychiatric disorders such as depression, dementia, Alzheimer's disease, schizophrenia, drug abuse - are all of great socio-economic impact but still very poorly understood with respect to brain chemistry and physiology. PET and SPECT are unique techniques for the investigation of these aspects of disease in vivo, provided that suitable radiotracers can be developed. Radiopharmaceuticals for the different types of serotonergic, glutaminergic and nicotinic receptors are badly needed analytical tools to diagnose and understand the disorders better, but also to test new drugs (drug development) and to follow up treatments.

To date for many of these receptors unfortunately no useful radiotracers have been established. This is particularly true for glutaminergic NMDA- receptor ligands where [11C]-ketamine and others proved to be useless for human studies, and as well for the nicotinergic receptor ligands. Some promising new substances like memantine (for the NMDA-receptor) or epibatidine (for the nicotinergic receptors) are becoming available and should be evaluated. For the serotonergic system receptor ligands for subtypes such as 5HT1A, 5HT2A and the reuptake are under evaluation. However much work needs to be done to elucidate the optimal subtype ligands and the functional importance of their receptors.

Several laboratories have high interest in the research field: Orsay, Villigen-PSI, Jlich, Stockholm, Hammersmith, Turku, Kuopio, Uppsala, Brussels, Aarhus.

2.Radioligands for heart receptors

Cardiac disease is of obvious socio-economic impact. There is substantial evidence for sympathetic drive in the aetiology of cardiac dysfunction (which is variously manifested in cardiomyopathy, myocardial infarction, syndrome X and sudden death). However, direct observation of the changes occurring in the sympathetic nervous system during disease progression is hampered by a lack of radioligands for measurements on pre- and postsynaptic adrenoceptors in living human subjects with PET or SPECT. In a first COST action significant progress was made on the development of radioligands and radiotracers which target the presynapse.

In this new Action we aim to focus on developing radioligands for post-synaptic adrenoceptors, such as a1 and á1, which are especially lacking. These might be expected to yield clinical information valuable in their own right and complementary to the information obtainable with presynaptic radioligands. Other receptors and binding sites implicated in cardiac disease will also be candidates for radioligand development. These include potassium channels and AT1 receptors. Specifically defined components of the project are defined as follows:

Development of a1-adrenoceptor radioligands. Currently there is no effective radioligand for PET or SPECT studies of a1-adrenoceptors in human myocardium. Novel a1-adrenoceptor ligands will be labelled with positron-emitters (carbon-11, fluorine-18, radioiodine) for evaluation as radioligands in vivo (rats, monkey and human). Evaluation will include assessment of metabolism and any species differences therein. Radioligands with subtype selectivity will be sought.

Development of á1 -adrenoceptor radioligands. An initial aim will be to develop new easily prepared 11C - and 18F -labelled, ligands based on s-CGP 12177, as a lead compound from synthesised homochiral precursors (e.g. ring N-methylated analogues, terminal N-methyl analogues). Radioiodinated versions will also be prepared for biological evaluation for PET and SPECT in rats, monkey, and humans. Evaluation will include elucidation of metabolism. Attempts will be made to understand the factors affecting the organ selectivity of radioligands (heart vs lung vs brain). Successful radioligands are guaranteed to find broad application in Europe for clinical studies in cardiology. European experience on the best working practices for the production of cardiac radiotracers and radioligands will also be exchanged.

Several centres are known to have an interest in this proposal (London, Stockholm, Turku, Gr"ningen, Orsay).

3.Radiolabelled biological active peptides

Peptides are a class of very potent native substances controlling important biological processes through high affinity receptors located on the cell membranes of target cells. Many properties make them attractive vectors for targeting cancer, a strategy already explored successfully for somatostatin. However since many frequently occurring and devastating tumours (small cell lung carcinoma, colon carcinoma or mengioma) do not express somatostatin receptors, it is imperative to search for alternative neuropeptide receptors expressed by these tumours. Recent evidence reports that such malignant lesions, like small cell lung cancer, colon carcinoma and certain mengiomas, express high affinity and density bombesin and neurotensin receptors on the tumour cell membrane.

For this purpose, peptide-based analogues with prolonged plasma life and preserved biological action will be properly modified to incorporate the radionuclide of choice. Tagging with 18F, 11C and 123I (or 99mTc) useful for PET and SPET respectively will be pursued. Efforts will also be undertaken to develop a therapeutically useful analogue carrying a radiotherapeutic nuclide (e.g. 90Y or 186Re).

Several centres are interested to collaborate: Rossendorf, Brussels, Padua, Villigen-PSI, Jlich, London, Uppsala, Oslo, Athens)

4.Radiolabelled Enzyme Inhibitors

Enzyme inhibition frequently constitutes the molecular basis for the effectiveness of powerful therapeutic agents. Progressively, new more powerful and more specific enzyme inhibitors are being designed and with them new therapeutic agents and consequently new radiotracers also for diagnostic purposes could be developed. Given the very strict criteria a biologically active molecule has to meet to become the basis of a radiotracer (cf. " the elements in a strategy for the development of enzyme-binding radioligands "), it is not surprising that only very few among the large number of tracer inhibitors known to enzymologists have given rise to radiopharmaceuticals. Among them the following should be mentioned:

-the autonomic radiopharmaceuticals that include the cholinesterase inhibitors (11C-physostigmine, 11C-THA) and the monoamine oxidase inhibitors (- irreversible: 11C-deprenyl, 76Br-pargyline - reversible: 123I-Ro43-0463);

-the cardiovascular radiopharmaceutical with 18F-captopril for visualising the angiotensine converting enzyme (ACE);

-the antiviral radiopharmaceuticals with the radiolabelled acycloviranalogues for imaging the DNA polymerase;

-the antineoplastic radiopharmaceutical such as 11C-methotrexate for dihydrofolate reductase imaging;

-the endocrine radiopharmaceutical such as 11C-metyrapone and 11C-etomidate for visualizing adrenal 11á-hydroxylase.

If we take into account the major role of enzymes in neurological, psychiatric, cardiac and endocrine disorders, it is obvious that an effort should be made to design radiopharmaceuticals for diagnostic purposes based on enzyme inhibitors.

Interested collaborators are laboratories in Vienna, Uppsala, Jlich, Orsay, Stockholm, Rome, Villigen-PSI, Tours.

5.Technetium chelates

Technetium-99m radiopharmaceuticals are used for a broad range of diagnoses in nuclear medicine. About 85% of nuclear medical diagnoses are performed with 99mTc labelled pharmaceuticals. Whereas the research in the past was mainly concerned with biological properties which allow relatively unspecific functional imaging as in brain or myocardium perfusion studies, nuclear medicine is now requiring more and more physiological information on low capacity, high specific molecular targets. To meet the requirements of new technetium-based compounds called the "third generation" of 99mTc radiopharmaceuticals, there is a demand for Tc tracers able to undergo molecular interactions with the target tissue. There is also a high interest to make available pharmaceuticals based on rhenium nuclides, such as 186Re and 188Re that are attractive for developing therapeutic radiopharmaceuticals.

Interest is focused on technetium-based receptor-binding species, whose design requires the availability of appropriate chelate systems for an optimal binding of the metallic nuclide.

A general approach to the above desired tracers involves the attachment of appropriate chelates to biologically relevant anchor groups. The project "Technethium chelates" will meet the requirements for new Tc tracers and the analogous rhenium compounds by doing basic research on new chelate systems that allow of the metallic nuclide at a coupling biological relevant anchor group (receptor-or enzyme- binding ligand or drug, peptide etc.) in such a way that alteration of structure and changes in biological properties are minimized. This requires appropriate chelate systems and methods for introducing the resulting Tc and Re chelates as biological relevant anchor groups into organic molecules.

The work will involve synthesis of new chelating systems having optimal properties (resulting complexes of low molecular weight/size, highly variable in structure and lipophilicity, absence of stereoisomers), complexation with technetium and rhenium (as the inactive analogous of technetium) as well as studies of relationships between physico-chemical parameters and biodistribution in animals.

In this field laboratories in Rossendorf, Padova, Athens, Villigen-PSI have expressed a high degree of interest.

D.Organisation and timetable

The administrative organization is based on a Management Committee with scientific secretariat. The whole Action will be divided in working groups along the tasks described in C. Each working group will be led by a coordinator. The duration of the Action should be ideally 5 years.

The Management Committee will ensure close contacts with the European Association of Nuclear Medicine (EANM) by presenting its results at the annual Conference and by inviting participation of EANM-members to the COST-Actions yearly symposia. Representatives of the industry target group, which consists of the pharmaceutical companies in Europe, will be contacted personally through the members of the COST-Action and the Management Committee will do its utmost to ensure that representatives of the companies take part in the annual symposia and as participants and/or invited guest speakers at the working group meetings. To ensure dissemination of the Action's results the proceedings of the annual symposia will be published in peer reviewed journals; preliminary contacts have been made. Furthermore papers on relevant results will be submitted to the respective scientific journals and presented as oral talks and posters on the yearly conferences of EANM and SNM (North American Society of Nuclear Medicine).

The detailed time table is shown in the following scheme:

E.Economic dimension

The complexity of different tasks needed to develop and evaluate New Radiopharmaceuticals makes it almost impossible for any single group to master such a work in reasonable time. Therefore the networking of the proposed COST-Action allows each group to focus its resources on tasks where it has expertise and to benefit from the others. Indeed a new radiopharmaceutical is developed most economically and efficiently by collaboration in a complementary effort. The limited budget of each group should not be spent on tasks undertaken by other groups. The present estimation indicates at least 20 institutions in 12 countries which are seriously interested. On the basis of 1 person/institution and year equivalent to EUR 45 000, the budget is at present about EUR 4,5 million for five years.

The development of effective new radiopharmaceuticals, might ultimately lead to early disease detection/diagnosis, better treatment strategies and assist in the development of more effective drugs. These achievements would lead to economic benefit in the prevention of morbid disease or costly treatment, and to introduce more efficient and precise methods of characterisation in drug development of the European Pharmaceutical Industry.

Program(-y)

IC-COST - European cooperation in the field of scientific and technical research (COST), 1971-

Temat(-y)

7 - Medical Research

Zaproszenie do składania wniosków

Data not available

System finansowania

Data not available

Koordynator

N/A

Wkład UE

Brak danych

Adres

Francja

Koszt całkowity