International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology最新文献

On the basis of its established in vitro characteristics, [³H]RX 821002 was evaluated in rats as an in vivo radioligand for central α₂-adrenoceptors. Estimates for in vivo binding potential, obtained by compartmental analyses of time-radioactivity data, ranged between 1.9 for hypothalamus and 0.2 for cerebellum, with a regional distribution in brain which was similar to that observed in vitro. Selectivity and specificity of the signal were checked by predosing with either the α₂-antagonists, idazoxan or yohimbine, the α₂-agonist, clonidine, or the α₁-antagonist, prazosin. Pretreatment of the rats with the selective neurotoxin, DSP-4, had no significant effect on [³H]RX 821002 binding, suggesting that the majority of labelled sites were situated post-junctionally. The studies indicate that [³H]RX 821002 can be used experimentally as an in vivo marker for central α₂-adrenoceptors. The size and rate of expression of the specific signal encourage the development and assessment of [¹¹C]RX 821002 for clinical PET studies.

To investigate whether bifunctional ligands containing chelating structures other than EDTA and DTPA and metallic radiotracers other than ¹¹¹In will reduce the non-specific radioactivity uptake in the liver during immunoscintigraphy, we synthetized an isothiocyanato-substituted phenolic polyaminocarboxylic acid (HBED-CI) for labeling of MAbs with ⁶⁷Ga, ¹¹¹In and ⁵⁹Fe. Biodistribution of HBED-CI-labeled MAbs was compared to that of ¹³¹I and ¹¹¹In-DTPA labeled MAbs in nude mice bearing tumors, which differ with regard to intracellular internalization and catabolism of the corresponding MAb-antigen complex. In the liver a continuous radioactivity excretion for ⁶⁷Ga-HBED-CI-labeled MAbs was observed with kinetics that parallel ¹³¹I clearance after administration of ¹³¹I-MAbs, while ¹¹¹In-HBED-CI-labeling led to a constant ¹¹¹In liver level quite similar to that of ¹¹¹In-DTPA-MAbs. In tumors, ⁶⁷Ga-HBED-CI-MAb uptake again paralleled that of ¹³¹I-MAbs, showing continuous accumulation in tumor tissues when internalization of the MAb-antigen complex was not involved. A much lower uptake, which peaked between 24 and 48 h, was found in the case of MAb-antigen internalization. ¹¹¹In of ¹¹¹In-HBED-CI- and ¹¹¹In-DTPA-labeled MAbs continuously accumulated in both types of tumors. Compared with ¹¹¹In-DTPA-MAbs, an improvement in tumor-to-liver ratios, due to the reduced liver radioactivity associated with ⁶⁷Ga-HBED-CI-labeled MAbs, could only be obtained with non-internalizing tumors. The time course of radioactivity distribution in the liver and in MAb-internalizing tumors after administration of ⁶⁷Ga-HBED-CI-, ¹¹¹In-HBED-CI- and ¹¹¹In-DTPA-labeled MAbs further indicates a dominating influence of the metallic radiotracer rather than the ligand on retention or excretion of radioactivity in MAb-catabolizing tissues.

The binding of ^99mTc to negatively-charged and neutral unilamellar lipid vesicles was investigated in the absence and presence of the ligand diethylenetriaminepentaacetic acid (DTPA) covalently attached to the headgroup of phosphatidylethanolamine at the surface of the membrane. Even in the absence of DTPA on the membrane surface, ^99mTc reduced by Sn bound to the membrane surface but rapidly dissociated from the vesicles in the presence of plasma in vitro. When DTPA was present on the membrane surface, dissociation of ^99mTc from the vesicle surface in plasma was much reduced. The dissociation of ^99mTc from the surface of negatively-charged vesicles was less than for neutral vesicles in the absence of ligand but was markedly greater than for vesicles containing the ligand DTPA, suggesting that the binding of ^99mTc to vesicles with surface-attached DTPA could not be explained solely on the basis of the negative charge provided by the DTPA. In vitro experiments using ¹⁴C-labeled lipids as well as in vivo imaging studies indicated that dissociation of ^99mTc from the surface of the vesicle did not arise predominantly because of lipid exchange with plasma components or due to cleavage of Tc-DTPA from the vesicle surface. For vesicles with surface-attached DTPA, ^99mTc dissociation from the vesicle surface in plasma was further reduced by addition of the antioxidant ascorbate.

The pharmacokinetics of [¹²³I]iomazenil (Ro 16-0154) in 5 healthy human volunteers were compared to those in 2 hypothermic and 3 normothermic anesthetized monkeys. Following intravenous injection in humans and monkeys, [¹²³I]iomazenil rapidly diffused outside the vascular bed and was cleared from the arterial plasma triexponentially. The clearance half-times in hypothermic animals were protracted to values closer to those of the human. [¹²³I]lomazenil was metabolized mainly to a polar radiometabolite (not extracted by ethyl acetate) in the human whereas an additional lipophilic radiometabolite was detected in the monkey. In vitro and in vivo studies showed that [¹²³I]Iomazenil established equal concentrations in association with the cellular and plasma component of the blood, indicating that the plasma clearance of [¹²³I]iomazenil mirrors that of the blood. Analysis of organs from a monkey given [¹²³I]iomazenil showed that the parent compound was actively taken up by peripheral organs; the polar radiometabolite accumulated mainly in the bile and the kidneys whereas the non-polar radiometabolite accumulated in the urine and kidneys. Greater than 90% of the radioactivity in the different regions of the brain was unchanged parent [¹²³I]iomazenil.

The exchange reactions of S-protected dithiol monoaminemonoamide (MAMA) ligands with Tc(V)-gluconate were investigated. Protection of the mercaptide sulfur atoms with acid, base and metal labile groups permitted complex formation of the MAMA ligands at a range of pHs. In general, the rate of complex formation was faster with the MAMA ligands than with the corresponding diamide dithiol (DADS) ligands. The rate of Tc complex formation depended on the nature of the sulfur protecting groups and on the position of the amine group with respect to the other donor groups in the ligands. Two isomeric ligands showed different mechanisms of complex formation. The isomer which gave the final Tc-dithiolate-MAMA complex in higher yield was shown to form a Tc-thioether-thiol-MAMA complex as an intermediate prior to metal-assisted S-dealkylation. The formation of the Tc-thioether complex intermediate at a lower temperature may account for the enhanced kinetics of chelation compared to the isomer which did not form the intermediate complex.

A kit has been developed to instantly prepare ^99mTc(V)—DMSA. The freeze-dried kit consisting of DMSA, stannous chloride and ascorbic acid in appropriate proportions, produces quality ^99mTc(V)—DMSA when mixed with 0.2 mL of 3.5% NaHCO₃ solution and 2–4 mL of [^99mTc] pertechnetate. The radiopharmaceutical characterized by chromatography with ITLC-SG in 0.9% saline and horizontal paper electrophoresis in 50 mM vernol buffer, pH 8.6, at a potential gradient of 15 V/cm showed a different mobility with respect to ^99mTc(III)-DMSA, a known agent for kidney imaging. The new agent exhibited less plasma protein binding as compared to that of ^99mTc(III)-DMSA. Biodistribution of the pentavalent DMSA in mouse demonstrated greater uptake in bone and muscle and lower uptake in liver and kidney with respect to trivalent DMSA. The soft tissue tumour specificity and its suitability for tumour scintigraphy was apparent from the scintigrams of mammary carcinoma in a C₃H Jax mouse and medullary carcinoma in a patient. Brain metastatic lesions were also visible in a breast carcinoma patient after administering him with the agent.

The status of the radiochemical development and biological evaluation of radioligands and tracers for PET studies of the serotonergic system is reviewed, indicating those agents with present value and those with future potential. Practical recommendations are given for the preparation of two useful radioligands for PET studies of central 5-HT₂ receptors, namely [¹⁸F]setoperone and [¹⁸F]altanserin. Though, it has not proved possible to recommend tracers or radioligands for the study of other aspects of the serotonergic system, prospects for future radiochemical development are indicated, especially for developing radioligands for the 5-HT re-uptake site, and for the 5-HT₁ and 5-HT₃ receptors.

The biologically active S-enantiomer of [N-methyl-¹¹C]citalopram was evaluated as a radioligand for in vivo labelling of the 5-hydroxytryptamine uptake site in brain, using ex vivo tissue counting in rats and positron emission tomography in man. In rats, the maximal signal for total versus non-specific binding was approx. 2 at 60–120 min after radioligand injection. Subsequent studies in man failed to identify a specific signal over a 90 min scanning period, due to prolonged retention of non-specific label.

The compound of interest, N-5-azido-2-nitrobenzoylaminomethyl-¹¹¹In-acetylacetone-α-cyclodextrin (CD) (V) was synthesized by the selective tosylation of α-CD to form 6-tosyl-6-deoxy-CD, which was then reacted with NaN₃ to form 6-azido-6-deoxy-CD (II). This was followed by catalytic hydrogenation to yield III. Compound III and ¹¹¹In-acetylacetone were mixed to form an inclusion complex, which was then reacted with N-5-azido-2-nitrobenzoyloxysuccinimide to yield compound V. Anti-melanoma MAbTP41.2 was added to compound V, followed by immediate photoreactivation labeling by u.v. light at 320 nm. The final product VI was purified from a Sephadex G-50 column. ¹¹¹In-DTPA-MAbTP41.2 was also prepared as a control.

Immunoreactivity via the cell-binding assay of VI was 87%, compared with 57% by the BADTPA method. Biodistribution in non-tumor rats yielded a liver concentration in %ID/g of 3.5, 1.7 and 1.0 for compound VI, compared to the 5.5, 5.2 and 3.1 for the BADTPA compound, at 4, 24 and 48 h post-injection, respectively.