No abstract available

[en] Short communication

[en] Full text: Cage ligands are very attractive for use in radiolabelling antibodies. Their synthesis is based around Co(III) octahedral co-ordination chemistry and they may be easily derivatised for attachment to antibodies. They are known to form kinetically inert metal complexes. Copper-64 (t_1/2 = 12.7 h) has been identified as having potential value in diagnostic and therapeutic application. Its positron annihilation radiation is useful for PET imaging, while its beta (E_max 578 keV, 37.2 %) emissions may also be suitable for therapy. In the current study, the new hexa-aza-cryptand, 1 -N-(4-amino-benzyl)-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]eicosane- 1,8-diamine, or SarAr, has been synthesised specifically for radiolabelling antibodies with ⁶⁴Cu and a kit formulation has been produced. The resulting radiolabelled immunoconjugate (⁶⁴Cu-SarArB-72.3) was injected into nude mice bearing LS174t colorectal carcinoma. Clearance of ⁶⁴CuSarAr-B72.3 from the liver and kidneys was typical of a whole IgG antibody. Tumour localisation was comparable to similar radiolabelled immunoconjugates (38± 5 % ID/g at 48 hours). Biodistribution studies of ¹²³I- and ¹¹¹In- radiolabelled B72.3 were conducted in the same animal model. MIRDOSE 3 was used to compare target to non-target dose of their analogous therapeutic counterparts (⁹⁰Y and ¹³¹I respectively) with ⁶⁴Cu-SarAr-B72.3. Total body dose for ⁶⁴Cu-SarAr-B72.3 was significantly lower (0.09 rad/mCi) than analogous products (¹³¹I-B72.3, 2.64 rad/mCi; ⁹⁰Y- B72.3, 2.387 rad/mCi) while still providing enough dose to small tumours to be potentially therapeutic. In order to assess therapeutic effect of ⁶⁴Cu, a biological study was conducted over a 12 month period. Nude mice bearing tumours between 3.5 - 5.5 mm in length were injected with various doses (0, 10, 20, 30, 40 MBq) of ⁶⁴Cu-SarAr-B72.3. Animals were regularly monitored for tumour size, animal mass, behavioural and physical abnormalities (e.g. movement / gait, food intake and hunching). Radiotoxic effects were monitored at predetermined time points (2 days, 1, 2, 3, 4 weeks, 2, 3, 4, 5 and 6 months). Indicators for the endpoint of the study were body weight loss > 20 %, rapid weight loss of > 10 % overnight, ulceration of tumour, limitation of normal behaviour (e.g. ability to feed or drink) and tumour size > 10 x 10 mm (UK Cancer Council). A significant extension of mouse life was achieved with doses of greater than 20 MBq (from 25 to 46 days for 30 MBq) with no major radiotoxic effects. Complexation of copper by SarAr is extremely fast making the production of ⁶⁴Cu-SarArB-72.3 immunoconjugate attractive for kit formulation and applicable for use in Nuclear Medicine Departments. Biological studies show the radioimmunoconjugate is stable in vivo and able to induce a therapeutic effect in tumour bearing animals. The shorter half life of ⁶⁴Cu and the MIRDOSE calculations support the potential of ⁶⁴Cu for use in treatment on an outpatient basis

[en] Iodine-131, ⁹⁰Y and ⁶⁴Cu are three radionuclides identified to have potential in radioimmunotherapy (RIT) applications Iodine-131 has been used extensively in RIT because it is readily available, inexpensive, and it chemistry for radiolabelling is relatively easy. However its high gamma emission (365 keV 81 %) together with its long half life (8 d) causes an undesirable high whole body radiation dose to the patient and creates problems associated with the hospitalisation of the patient and radiation exposure to the radiopharmacy and medical staff. Yttrium-90 has a high energy beta that has a long range in tissue (12 mm), hence it is considered( best for the treatment of large tumours (I - 2 cm). However, with the absence of an imaginable γ emission, imaging and dosimetry calculations must be calculated with the analogous ¹¹¹In labelled product. Poor stability of ⁹⁰Y labelled antibodies may result in a dose to the patient's bone marrow, due to normal accreditation of free ⁹⁰Y. Copper-64 has a 12.7 h half life and emits positrons that offer the advantage of use in Positron Emission Tomography (PET). The greater resolution of PET allows more accurate monitoring ol tissue uptake and optimum use for therapy. Copper-64 β max energy of 0.58 MeV (37 %) is slightly lower, though comparable to ¹³¹I, and hence could be expected to administer similar therapeutic effect. Now that high specific activity ⁶⁴Cu is readily available at the National Medical Cyclotron, it was thought useful to assess the potential of this radionuclide in RIT. A series oi radioimmunoconjugates of B72.3 antibody incorporating ¹²³I, ¹¹¹In and ⁶⁴Cu were prepared and their biodistribution in nude mice bearing colorectal tumours evaluated. This data was used to estimate the dosimetry of the analogous ¹³¹I, ⁹⁰Y, and ⁶⁴Cu products in humans assuming similar pharmacokinetics in both species. A comparison of the therapeutic dose to the target and nontarget sites was made and consideration given to the most appropriate regime for optimum patient management

[en] Full text: ⁶⁴Cu decays by β⁺ (0.655 MeV; 19%) and β^- (0.573 MeV; 40%), which enables both imaging by PET and potential for radiotherapy. The National Medical Cyclotron routinely produces high specific activity ⁶⁴Cu and we have developed a new bifunctional chelator for use in the radiolabelling of antibodies and peptides. Initial studies have involved the radiolabelling of B72.3 antibody. Complexation of the ⁶⁴Cu is complete in < 5 min and the radioimmunoconjugate is stable in human sera for up to 8 days. Specific activities of>370 MBqmg^-1 have been achieved and the immunoreactive fraction maintained. Biodistribution studies in LS174T tumour-bearing nude mice have shown good localization at the tumour site (38 ± 5% ID/g at 48 h) and tumour:blood ratios of 2.1 ± 0.5 at 48 h. Clearance from the blood is biphasic (α-phase 7.1 ± 0.2 hours, β-phase 72 ± 6 h). The pharmacokinetics of this radioimmunoconjugate was compared with ¹³¹I1 and ¹¹¹ln labelled B72.3. MIRDOSE 3 calculations were used to estimate the dosimetry of the therapeutic analogues (¹³¹I, ⁹⁰Y and ⁶⁴Cu) of the respective radiolabelled antibodies in humans. The biodistribution of the radionuclide analogues was assumed to be the same as their experimental product (e.g ¹¹¹In vs ⁹⁰Y labelled antibody), and their pharmacokinetics in mice similar to that in humans. Dose to the critical dose organs (liver and kidneys) was shown to be ⁶⁴CU < < ¹³¹I < ⁹⁰Y. Consideration of the most appropriate regime for optimum patient management was assessed and will be outlined

[en] Low acid concentration aqueous/organic mixtures with an anion exchange resin (AG1-X8) have been used to separate carrier-free ⁶⁴Cu from the by-products of cyclotron produced ⁶⁷Ga. The specific activity of the ⁶⁴Cu (5 x 10¹⁴ Bq/g) was found to be higher than that reported previously. Trace levels (<1%) of ⁶⁷Cu were also present. The new separation method is easier and faster (2 hours) than those currently employed in routine purification of both ⁶⁷Cu and ⁶⁴Cu production. We believe that the new method is the first reported use of organic solvents in the separation and purification of these radioisotopes and represents the first effort towards full characterisation of by-products for appropriate waste management. (orig.)

[en] Full text: Copper-64 has been identified as having potential use in diagnostic and therapeutic applications. Its annihilating radiation is useful for PET, while its beta, auger emissions may lend themselves for use in therapy. A new bifunctional chelator for radiolabelling antibodies with ⁶⁴Cu has been developed. The conjugation of the bifunctional chelator to the B72.3 antibody is readily mediated using the commercially available 1-ethyl-3-(3-dimethylaminopropyl) carboiimide. HCI (EDC). This technology is quite versatile and may be transferred for radiolabelling other molecular recognition units provided the appropriate reactive sites are available. Once the immunoconjugate is formed complexation of the ⁶⁴Cu is rapid (> 99% within 5 mins). The radioimmunoconjugate is stable (less than 1% breakdown) in vitro [acetate buffer (pH 5.0), 4 deg C ] for up to 190 hrs. Biodistribution studies in nude mice bearing colorectal tumours (LS 174t) showed good localisation of the radioimmunoconjugate to the target site (up to 38% ID/g at 48 hr) and tumour to blood ratios of 2.1 ± 0.5 at 48 hrs. These results are comparable those reported for ¹²⁵I and ¹¹¹In labelled antibody

[en] Short communication

[en] Full text: A novel approach for the delivery of therapeutic doses from ¹⁶⁶Ho to cancerous tissue is via the decay of its parent, ¹⁶⁶Dy. When designing radioimmunoconjugte, a crucial question is to determine whether the ligand used in the radiolabeling process is capable of holding the ¹⁶⁶Ho on decay of the parent, ¹⁶⁶Dy. In this study, two pendant arm macrocycles 1, 10-Diaza-4, 7, 13, 16-tetraoxacyclooctadecane-N, N'-diacetic acid, (DACDA) and 1, 10-Diaza-4, 7, 13-trioxacyclopentadecane-N, N'-diacetic acid, (DAPDA) that were reported to forms reasonably stable complexes with Dy and Ho, were synthesised. The synthesis of the two pendant arm macrocycles was first attempted using methods outlined by Chang and Rowland. The yields obtained through this method were low (10 % for both ligands) and it was considered important to investigate alternative approaches to the synthesis. The new method involved an alkylation reaction in the presence of acetonitrile and sodium bicarbonate. The method took considerably less time and the yields increased to 88 %. The ligands were characterised using ¹H NMR, ¹³C NMR and mass spectrometry. The chemical and radiolytic stabilities of ¹⁶⁶Dy and ¹⁶⁶Ho complexes of the two ligands were investigated at pH = 5 and the ligands potential for use in the in vivo generator system evaluated