99mTc Radiopharmaceuticals Research Articles

Hydroxamamide as a chelating moiety for the preparation of 99Tcm radiopharmaceuticals (I).

Hydroxamamides contain a nitrogen and an oxygen as donor atoms, and can be synthesized by the simple reaction of nitriles with hydroxylamine. Benzohydroxamamide (BHam) was investigated as a new ligand for 99Tcm. The yield of the 99Tcm-BHam complex was determined by thin-layer chromatography using cellulose strips. A high yield of the complex was obtained at room temperature over a wide pH range, even at BHam concentrations as low as 5 x 10(-7) M. Cellulose acetate electrophoresis indicated that the complex was uncharged. When the 99Tcm-BHam complex was injected into mice, it was cleared gradually from the blood by means of the hepatobiliary system with low urinary excretion. Uptake by the stomach and the spleen was low. These results demonstrate the high affinity of BHam for 99Tcm and the high stability of the 99Tcm-BHam complex. The hydroxamamide group may be a promising chelating moiety for designing new 99Tcm radiopharmaceuticals.

A new, general synthetic route to multidentate N,S ligands for use in technetium-99m radiopharmaceuticals. Preparation of diamido disulfur, diamino dithiol, and tripodal N3S3 prototypes. Comparative biodistributions of [99mTcVO-DADS]- analogs which contain 5,5,5- and 5,7,5-membered chelate ring systems

A new, versatile synthetic route to a variety of tetradentate N2S2 and hexadentate N3S3 ligands for use in technetium-99m radiopharmaceuticals has been developed. The key reaction employs 1-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline (EEDQ) for coupling an appropriate di- or triamine with S-protected thioglycolic acid. Selected DADS (diamido disulfur) and DADT (diamino dithiol) and analogues derived from ethanediamine-1,2 and butanediamine-1,4, as well as a tripodal N3S3 analogue, were synthesized in high yield. The labeling of DADS analogue ligands derived from butanediamine-1,4 (DADS-bn) with 99mTc results in a single radiochemical product, or the expected number of stereoisomeric products. FAB MS analysis, using 99Tc, indicates that DADS-bn ligands form a tetradentate 5,7,5-membered ring chelate system with the monooxo Tc(V) core: [TcO-DAD-bn]-. In rat biodistribution studies the DADS-en and DADS-bn complexes show very similar biological activity. Phenyl substituents on the 7-membered ring give rise to a 99mTc complex of increased lipophilicity, increased liver uptake, and minimal hepatobillary clearance. Thus, new classes of DADS ligand analogues which contain a 5,7,5-membered chelate ring system are readily synthesized and labeled with 99mTc to form stable complexes. The presence of the 7-membered chelate ring allows for facile introduction of pendant groups into the ligand system, and thus for a ready route to control the biodistribution of the resulting 99mTc radiopharmaceutical. The 99mTc labeling of the DADT analogues derived from butanediamine-1,4 provided to be erratic, despite the use of a variety of labeling techniques; the larger ring system of DADT-bn apparently does not favor the monooxo Tc(V) core and appears to generate a mixture of mono- and dioxo Tc(V) cores.

Application of a macromolecular Sn (II) complex to the preparation of 99mTc radiopharmaceuticals

AbstractTo develop insoluble Sn2+ complexes for the preparation of 99mTc radiopharmaceuticals, the adsorption of Sn2+ to macroreticular chelating ion exchange resins having various functional groups was investigated. Among them, a resin containing aminophosphonic acid groups showed a high adsorption capacity for Sn2+, which was bound strongly to the resin by chelation. This macromolecular Sn2+ complex was very stable against hydrolysis and oxidation, and could be applied satisfactorily for the reduction of 99mTc.

99Tcm radio-pharmaceuticals for the X-ray fluorescence assessment of gold in vivo

From the work presented it is concluded that intravenously administered 99Tcm radiolabelled pharmaceuticals would be suitable sources for X-ray fluorescence (XRF) studies of gold in the kidney. The target minimum detectable level of 50 mu g g-1 would be achieved with a detector of sufficient area using significantly less than the activity administered to patients undergoing diagnostic renal studies. Of the two radio-pharmaceuticals in routine use locally for kidney studies, DMSA proved to be the better drug, as to obtain the same XRF yield higher activities of DTPA need to be administered.

Development of macromolecular Sn(II) complex for preparation of 99Tcm radiopharmaceuticals

Macromolecular Sn(II) complex (R-Sn) was developed using a chelating resin containing aminophosphonic acid groups as a reducing agent of 99Tcm(VII) in the preparation of 99Tcm radiopharmaceuticals. Since Sn(II) was bonded strongly to the resin by chelation, release of Sn from R-Sn was rarely observed in saline solution. 99Tcm labelling with a yield greater than 90% was performed by mixing R-Sn, 99Tcm pertechnetate solution and a ligand, such as human serum albumin and diethylenetriamine pentaacetic acid, for a short time. The 99Tcm radiopharmaceuticals were almost free from Sn(II) and the reducing activity of R-Sn was quite stable despite long-term storage without any special care.

Fifteen Years of Radiological Protection Experience in a Regional Radiopharmacy

Radiological protection experience in a regional radiopharmacy, currently handling 28.5 TBq (770 Ci) 99mTc y-1, is reviewed for the period 1974-1988. The results of personnel monitoring have shown a downward trend (by more than a factor of two) in radiation exposure of individual staff members, despite the workload per person [6000 GBq (162 Ci) 99mTc y-1] remaining virtually constant. Adequate staff selection and training contribute to the reduction in dose. A significant reduction in dose to the eyes was achieved by installing lead glass screens in the radiopharmacy work stations, and tungsten syringe shields reduced radiation dose to the hands. The use of commercially available kits for producing 99mTc radiopharmaceuticals, rather than relying on in-house preparations that require more operator handling, has also contributed to reduction in radiation exposure. Internal contamination of staff members with 125I was markedly reduced when the practice of sub-dispensing high-specific activity solutions of the radionuclide was discontinued. Annual doses from external radiation currently average less than 6 mSv (600 mrem) to the trunk, less than 7 mSv (700 mrem) to the eyes, and 50 mSv (5 rem) to the hands. Internal contamination of personnel with 125I, 131I, and 99mTc, as detected by thyroid and whole-body monitoring, contributed less than 65 mSv y-1 (6.5 rem) to the thyroid gland and less than 0.1 mSv y-1 (10 mrem) to the whole body.

Quantitative study of the structure-stability relationship of Tc vO(III) complexes

This paper describes the quantitative structure-stability relationship of Tc vON 2S 2 compounds using a stability indicator based on the solid angle factor sum (SAS)_for predicting the in vitro stability. The SAS values of six Tc vON 2S 2 and one Tc vON 4 ( d,l-HMPAO) complexes were calculated from their x-ray crystallography data. The rank order of in vitro stability of these compounds, as measured by ligand exchange reaction, is directly related to that of the SAS values. The SAS values are potentially useful for predicting stability and designing new 99mTc radiopharmaceuticals.

Analytical artifacts in quality control of 99mTc radiopharmaceuticals

Control of the radiochemical purity of radiopharmaceuticals labelled with technetium is frequently carried out by chromatographic methods, using paper as support and acetone as solvent. These methods are affected by various artifacts such as the drop of radiopharmaceutical drying out in the open air prior to chromatography onset, thus altering the normal behaviour of pertechnetate. This alteration may significantly modify the result obtained, but is only present in some chromatographic systems, such as paper/acetone or MEK; it does not affect the oxidation status of technetium.

Technetium-99m Radiochemical Assay by Rapid Filtration: A Superior Alternative to Chromatography

A new method for simultaneously measuring radiochemical purity and estimated lung trapping of colloidal technetium-99m (99mTc) radiopharmaceuticals is described. The method employs a small filtration device comprised of two stacked membrane filters, differing in membrane composition and in pore size, situated over a filtrate collection vial. Specifically, an 8-microns pore polycarbonate membrane filter is situated above a 0.22-microns pore mixed-cellulose-esters membrane filter. For assay, a diluted aliquot of radiopharmaceutical is passed through the filtration device. Technetium-99m radioactivity on the membranes and in the vial is then measured. The polycarbonate filter traps and quantitates lung-capillary-occluding particles. The mixed-cellulose-esters filter traps and quantitates radiocolloid particles irrespective of relative size. The filtrate contains free pertechnetate. Within 4 min, this method yields results that compare well with those achieved by conventional techniques. The method works equally well for large colloidal particles [( 99mTc]stannous colloid), intermediate-size particles [( 99mTc]sulfur colloid), and small-size particles [( 99mTc] antimony trisulfide colloid).

Routine determination of radiochemical purity of 99mTc-MIBI

The manufacturer recommends that the radiochemical purity of 99mTc-MIBI be determined with alumina TLC plates developed in ethanol, but for routine use this is slow and requires care. After comparing a variety of systems, we obtained equivalent results using ITLC-SG strips developed with saline to determine [ 99mTc]pertechnetate and with acetone to determine 99mTc colloid; % 99mTc-MIBI was determined by difference from 100%. These separations are the opposite of those obtained with the routine polar 99mTc radiopharmaceuticals. Equivalent results were obtained even more rapidly by extracting 99mTc-MIBI from water into chloroform.

Interaction of some sterilizing filter materials with some technetium-99m radiopharmaceuticals

The retention of a variety of 99mTc radiopharmaceuticals on four different sterilizing filter membranes has been evaluated. It was demonstrated that some 99mTc radiopharmaceuticals show significant retention on certain types of sterilizing filters, presumably due to interactions between the radiopharmaceutical and the filter material.

The chemistry of rhenium and technetium as related to the use of isotopes of these elements in therapeutic and diagnostic nuclear medicine

The β emitting isotopes 186Re and 188Re are logical choices on which to base therapeutic radiopharmaceuticals that might be expected to be analogous to diagnostic radiopharmaceuticals based on 99mTc. However, the chemistry of rhenium is sufficiently different from that of technetium so that the development of Re radiopharmaceuticals often cannot be predicated on the known chemistry and biological behavior of 99mTc radiopharmaceuticals. The relevant chemical differences involve the greater stability of the higher oxidation states of Re (and thus the greater tendency of reduced Re radiopharmaceuticals to undergo re-oxidation to perrhenate), and the greater substitution inertness of reduced Re complexes. These differences are illustrated (1) in the preparation and use of 186Re (Sn)-HEDP and 99mTc(Sn)-HEDP diphosphonate radiopharmaceuticals designed, respectively, for palliative therapy and diagnosis of metastatic cancer to bone, and (2) in the preparation and biodistribution of tr-[ 186Re(DMPE) 2Cl 2] + and [ 186Re(DMPE) 3] +, analogs to the potential myocardial perfusion imaging agents tr-[ 99mTc(DMPE) 2Cl 2] + and [ 99mTc(DMPE) 3] +. [HEDP = (1-hydroxyethylidene)diphosphonate; DMPE = 1,2-bis(dimethylphosphino)ethane].

Studies on commercially available 99Mo/ 99mTc radionuclide generators—II. Operating characteristics and behavior of 99Mo/ 99mTc generators

Two 99Mo/ 99mTc generators from each of the four U.S. manufacturers were tracked through their clinical lifetimes by monitoring elution efficiency and the amount of total technetium per mCi 99mTc in the individual generator eluants. The resulting values of (moles Tc)/(mCi 99mTc) were compared to theoretical values calculated using an existing nomograph. The nomograph consistently underestimates the mass of total technetium in generator eluants by 25–300%. Also, there are statistically significant ( P < 0.05) differences in the amount of total technetium per mCi of 99mTc in the eluants from generators of different manufacturers. These results are interpreted in terms of absorbed radiation dose causing a transient holdback of 99mTc and in terms of excess technetium being loaded onto the generators at the time of manufacture. The relevance of these experimental results to the preparation of reduced 99mTc radiopharmaceuticals is discussed.

Radiation exposure in nuclear cardiovascular studies.

Nuclear cardiovascular studies are being introduced in almost every Nuclear Medicine Department. The number of studies performed per week is increasing very rapidly. The physical characteristics including the specific gamma ray constant for radionuclides used in cardiovascular studies are listed. The radiation dose estimates to different organs of a patient administered with 201Tl and 99mTc radiopharmaceuticals are shown. The radiation levels measured around patients administered with 201Tl chloride, 99mTc HSA (human serum albumin), and 99mTc-MDP (methylene diphosphonate) are within the permissible limits. Radiation doses to different organs from nuclear cardiovascular studies are less than those associated with fluoroscopy, particularly cardiac catheterization. However, the gonadal doses received from cardiac catheterization and angiocardiography are considerably lower than nuclear cardiovascular studies.

An examination of the labelling of intact human erythrocytes with 99mTc.

Summary. 99mTc radiopharmaceuticals are now in common use in diagnostic nuclear medicine although rather little is known about the chemical structure of the Tc‐ligand complexes formed when Tc is bound to organic compounds. We examine 99mTc‐labelled erythrocytes and find that proteins in addition to haemoglobin are labelled with 99mTc, possibly through their sulphydryl groups. This contrasts markedly to the labelling of erythrocytes with 51Cr where only haemoglobin is labelled.

Survey of 99mTc contamination of laboratory personnel: hand decontamination.

Decontamination after exposure to various 99mTc radiopharmaceuticals was tested with serial hand washings both with and without soap. All radiopharmaceuticals were removed more effectively with soap and the degree of decontamination related closely to the number of washings. The affinity of the radiopharmaceuticals for the skin varied, depending upon the labeled material, and only macroaggregated albumin was effectively removed to less than 1% of its original activity with soap. Activity transfer to the opposite hand could be substantial with macroaggregated albumin and sulfur colloid if soap is not used.

Radionuclide emission computed tomography of the body of laboratory animals.

Selective studies in the monkey and baboon demonstrate the normal physiologic distribution of 99mTc radiopharmaceuticals using single-photon emission computed tomography. The cases demonstrated the ability of the Cleon Transverse Section Brain Imager TM to do emission computed tomography of various organs. This experience shows what can be expected when equipment for emission computed tomography of the body becomes available for patient studies.

Pediatric Nuclear Medicine

The subspecialty of pediatric nuclear medicine has rapidly developed since the last discussion1 of the indications for and value of radionuclide imaging in children. New imaging techniques, equipment, and radiopharmaceuticals have stimulated this rapid growth. Bone imaging with the 99mTc phosphate compounds has been applied to evaluate benign as well as malignant processes. Tumor detection and staging have been accomplished with various 99mTc radiopharmaceuticals. Vesicoureteral reflux is more effectively detected with direct radionuclide cystography. A major role in the detection and evaluation of cardiac abnormalities and shunts has been achieved with nuclear techniques. Recognition of this remarkable growth and development is found in the publication of several books on pediatric nuclear medicine, the presentation of pediatric nuclear in medicine seminars, and formal sessions at the Society of Nuclear Medicine annual meeting.2-6 This brief discussion will hopefully keep the pediatrician aware of the expanding role that radionuclide techniques have in the management of pediatric patients.

Electrolytical labeling of 99mTc radiopharmaceuticals

Electrolytical labeling of 99mTc radiopharmaceuticals

Instant 99mTc Compounds

SummaryThe full potential use of technetium has not been achieved despite its ideal physical properties, dosimetry and availability because of the complex preparations required for 99mTc radiopharmaceuticals. One of the goals of our work is to develop techniques for the preparation of high-purity 99mTc compounds which can be easily prepared, ideally by adding pertechnetate to a prepared solution.The use of stannous ion as reducing agent for technetium makes it possible to obtain such one-step, high-purity products. All non-radioactive components can be premixed in a single vial before addition of the radioactive pertechnetate. No final pH adjustment, further chemical manipulation or purification is required.Procedures for two instantly labeled compounds have been developed to date: 99mTc DTPA and 99mTc HSA. The 99mTc DTPA is prepared by adding pertechnetate to a previously prepared solution of stannous ion and CaNa3 DTPA which has been stored at pH 4. The 99mTc HSA is prepared by adding pertechnetate to a solution of stannous ion and HSA. The parametric variations and analytical techniques involved in formulating these procedures are described. It appears that development of kits for other biologically interesting compounds may be possible using similar procedures.