Would you like to tell us about a lower price? The work presented here is based upon contact with excellent scientists who did not measure their time sparingly to be of assistance. In this respect, I am particularly indebted to a number of people. Abramovici, Professor S. Orloff and Professor R. The latter benefited also from the efforts of Dr. Streule who supervised the cross-over study upon which the final conclusions have been based.
Kriegel, kind enough to enable me to complete this particular part. I am also indebted to Dr. Preferably, such complexes comprises gallium in the Ga III oxidation state. Such gallium-NOTA complexes are known in the art. Recombinant HSA has the advantages of capability of reproducible manufacture under GMP Good Manufacturing Practice conditions, and avoidance of the hazards associated with blood-derived products.
Hence, recombinant HSA is preferred. The HSA is preferably in the form of either:. Firstly, HSA is initially conjugated to a bifunctional chelator, NOTA, and secondly the conjugate is labeled with 68 Ga via a complexation reaction of 68 Ga with the chelator. The 68 Ga complexation is described in the fourth aspect below. In a second aspect, the present invention provides a radiopharmaceutical composition which comprises the radioactive gallium complex of the first aspect, together with a biocompatible carrier medium.
Preferred aspects of the radioactive gallium complex in the second aspect are as described for the first aspect above. The "biocompatible carrier medium" is a fluid, especially a liquid, in which the gallium radio metal complex is suspended or dissolved, such that the composition is physiologically tolerable, i. The biocompatible carrier medium is suitably an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic ; an aqueous solution of one or more tonicity- adjusting substances eg.
The biocompatible carrier medium may also comprise biocompatible organic solvents such as ethanol. Such organic solvents are useful to solubilise more lipophilic compounds or formulations. Preferably the biocompatible carrier medium is pyrogen-free water for injection, isotonic saline or an aqueous ethanol solution. As indicated above, the pH of the biocompatible carrier medium for intravenous injection is suitably in the range 4.
In a third aspect, the present invention provides a NOTA-HSA conjugate useful in the preparation of the radioactive gallium complex of any one of the first aspect, or the radiopharmaceutical composition of the second aspect, wherein said conjugate has either:. NOTA is functionalized through modification of one of its carboxylates or modification of one of the carbon atoms on its cyclic backbone.
The reactive group is connected via a short spacer Scheme 1. Such bifunctional chelators can be prepared as described by Jeong et al [J. Scheme 1. Chemical structures of active esters of NOTA. In a fourth aspect, the present invention provides a method of preparation of the radioactive gallium complex of the first aspect, which comprises reaction of the NOTA- HSA conjugate of the third aspect, with a suitable source of 68 Ga. That is crucial when producing radiopharmaceuticals based on fragile macromolecules.
The 68 Ga-labeled products do not require purification since the radioactivity incorporation is quantitative and the product can be prepared in HEPES buffer which is eligible for human use. The 68 Ga complexation method is also amenable for automation. The excellent thermodynamic stability of the NOTA complex allows the use of NOTA conjugates in vivo with minimal potential for leaching and deleterious side effects.
It is important to note here that 68 Ga-NOTA labelling occurs at room temperature in about 5 to 10 minutes. Further details of suitable reaction conditions for the 68 Ga labeling of the fourth aspect are provided by Jeong et al [J. Scheme 2. The method of the fourth aspect is preferably automated, more preferably using an automated synthesizer apparatus.
By the term "automated synthesizer" is meant an automated module based on the principle of unit operations as described by Satyamurthy et al [Clin. The term 'unit operations' means that complex processes are reduced to a series of simple operations or reactions, which can be applied to a range of materials. Such automated synthesizers are preferred for the method of the present invention especially when a radiopharmaceutical product is desired.
Commercial automated synthesizers also provide suitable containers for the liquid radioactive waste generated as a result of the radiopharmaceutical preparation. Automated synthesizers are not typically provided with radiation shielding, since they are designed to be employed in a suitably configured radioactive work cell.
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The automated synthesizer preferably comprises a cassette. By the term "cassette" is meant a piece of apparatus designed to fit removably and interchangeably onto an automated synthesizer apparatus, in such a way that mechanical movement of moving parts of the synthesizer controls the operation of the cassette from outside the cassette, i. Suitable cassettes comprise a linear array of valves, each linked to a port where reagents or vials can be attached, by either needle puncture of an inverted septum-sealed vial, or by gas-tight, marrying joints.
Each valve has a male- female joint which interfaces with a corresponding moving arm of the automated synthesizer. External rotation of the arm thus controls the opening or closing of the valve when the cassette is attached to the automated synthesizer. Additional moving parts of the automated synthesizer are designed to clip onto syringe plunger tips, and thus raise or depress syringe barrels. The cassette is versatile, typically having several positions where reagents can be attached, and several suitable for attachment of syringe vials of reagents or chromatography cartridges eg.
The cassette always comprises a reaction vessel. Such reaction vessels are preferably 1 to 10 cm 3 , most preferably 2 to 5 cm 3 in volume and are configured such that 3 or more ports of the cassette are connected thereto, to permit transfer of reagents or solvents from various ports on the cassette. Preferably the cassette has 15 to 40 valves in a linear array, most preferably 20 to 30, with 25 being especially preferred. The valves of the cassette are preferably each identical, and most preferably are 3-way valves. The cassettes are designed to be suitable for radiopharmaceutical manufacture and are therefore manufactured from materials which are of pharmaceutical grade and ideally also are resistant to radiolysis.
In a fifth aspect, the present invention provides a method of diagnostic imaging in vivo of a mammalian subject, wherein said method comprises:. Preferably, the tracer comprises the radiopharmaceutical composition. When a positron meets an electron, both are annihilated and the result is a release of energy in form of gamma rays, which are detected by the PET scanner.
By employing natural substances that are used by the body as tracer molecules, PET does not only provide information about structures in the body but also information about the physiological function of the body or certain areas therein. Gamma radiation produced from the positron-emitting radioisotope is detected by the PET scanner and reflects eg.
Generally, a tracer is chosen that will accumulate in the area of interest, or be selectively taken up by a certain type of tissue, e. Scanning consists of either a dynamic series or a static image obtained after an interval during which the radioactive tracer molecule enters the biochemical process of interest. The scanner detects the spatial and temporal distribution of the tracer molecule. PET also is a quantitative imaging method allowing the measurement of regional concentrations of the radioactive tracer molecule.
In the method of diagnostic imaging of the fifth aspect, when the HSA is in the form of nanometre sized particles, the site of interest within the subject is preferably a site of infection or a sentinel node. In the method of diagnostic imaging of the fifth aspect, when the HSA is in the form of micrometre sized particles which are macroaggregated, the site of interest within the subject is preferably pulmonary. The tracer of the fifth aspect can be injected intravenously, or it can be administered directly to a tumour in order to follow the cell leakage to the lymph nodes and the spread of the disease.
Dynamic PET scanning of the heart from minutes after injection will provide data on cardiac output, the central blood volume and other aspects of systemic. The 68 Ga-HSA tracer will equilibrate in the intravascular compartment within minutes. A PET scan starting from 2 minutes after injection will provide information on the regional blood volume of the tissue. Determination of [ 68 Ga] in whole blood at 2 min post-injection will provide a measurement of whole-body blood volume.
The whole blood measurement of radioactivity concentration can be taken from the image data a region of interest in the heart cavities or the aorta , or from a discrete venous blood sample for measurement in a well counter cross-calibrated to the PET scanner. If the radioactive concentration is measured in the plasma fraction of whole blood, the whole-body plasma volume and the haematocrit can be calculated.
Approximately 2 minutes post-injection, the 68 Ga-HSA tracer has equilibrated in the entire blood volume. The scanner is then positioned with a specified part of the body brain, lungs, heart, tumor etc. Images obtained from regional scanning can be converted to parametric images of blood volume by normalising concentration in images to the concentration of [ 68 Ga] in whole blood. If blood volumes in larger parts of the body needs to be assessed, a whole-body PET protocol could be applied.
If scanning of the heart regions is applied with ECG-gated acquisition, a cine sequence software describing the volumes of the heart cavities could be constructed. The 4D- PET volume would be suitable for automated evaluation of chamber volumes and ejection fractions. This measurement would be clinically important in fibrotic diseases such as lung fibrosis and liver fibrosis, but would also be useful for advanced PET studies of other tissues for assessment of partial tissue volumes. Islamic worship.
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