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The new water-soluble photosensitizer 5,10,15,20-tetrakis[3,4-bis(carboxymethyleneoxy)phenyl]chlorin (T3,4BCPC) has been prepared, characterized and labeled with 99mTc radionuclide. The radiotracer was evaluated for tissue distribution in Wistar rats. Accumulation of administrated activities in the liver, kidney, bladder and large intestine at 4 h post-injection indicated that the labeled ligand was largely eliminated through the renal and partly through the hepatobiliary system. In vivo biodistribution studies of the labeled compound were carried out in rodent and murine tumor models in comparison with other tumor-seeking radiopharmaceuticals such as 99mTc(V)-dimercaptosuccinic acid (DMSA), 201thallous chloride (TlCl) and 99mTc-citrate using a gamma camera computer system. In N-nitrosomethylurea (NMU)-induced rat mammary tumors, the labeled ligand showed a five-fold tumor to muscle (T/M) ratio compared to 99mTc(V)-DMSA (3-fold) and 201TlCl (3-fold). In the case of C(3)H/J virus-induced spontaneous mammary tumors, the differences were not marked. However, in the transplanted rat C(6)-glioma, the T/M ratio of the labeled compound was appreciably higher (four-fold) than that noted with 99mTc(V)-DMSA (two-fold), 201TlCl (three-fold) and 99mTc-citrate (more than three-fold). These findings suggest that the radiolabeled T3,4BCPC may have potential for the detection of cancer. In order to ascertain the efficacy of the compound for photodynamic therapy applications, a preclinical PDT study was carried out in fibrosarcoma-bearing mice after injecting 5.0 mg/kg body weight of the T3,4BCPC. A laser dose of 20 mW for 60 s resulted in 80% destruction of tumors. These data suggest that this molecule could be useful for PDT of cancer. The labeled agent could also be useful in monitoring the progression/regression of tumors before, during, and after chemotherapy, radiation therapy or PDT.

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A new water-soluble cyclam acid porphyrin (CAP), 5,10,15,20-tetrakis [4-[4',8',11'-tris(carboxymethyl)-1'-(1',4',8',11'-tetraazacyclotetradecane)amidomethyleneoxy]phenyl] porphyrin has been synthesised, characterised and labelled with 99mTc. In vivo distribution studies were performed in C6-gliomas and N-nitroso-N-methylurea (NMU) induced mammary tumour bearing rats and scintiimages were obtained at 5 h post-administration of the labelled ligand using gamma camera computer system. Tumour to muscle (T/M) ratios were determined and compared with currently available tumour seeking radiopharmaceuticals such as 99mTc(V)-DMSA, 99mTc-Citrate and 201TlCl. In the case of NMU induced mammary tumour rats the ratios were 6.93, 1.97, 5.30 and 3.29; while in the case of C6-gliomas the ratios were 5.58, 2.18, 3.96 and 3.02 for 99mTc-CAP, 99mTc(V)-DMSA, 99mTc-Citrate and 203TlCl, respectively.

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We have synthesized two water soluble dendritic porphyrins, termed DP1 and DP2 and have successfully radiolabeled them with 99mTc. These 99mTc-labeled porphyrins were administered to C6-glioma tumor bearing Wistar rats and scintiimaging and biodistribution studies were carried out. Tumor to muscle ratios of DP1 and DP2 were 8.0 and 9.7, respectively. These molecules may have potential for tumor imaging and diagnosis and may even prove useful as photosensitizers in photodynamic therapy applications.

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Technetium-99m labeled cyclam N-2'-methoxyethyl-2-(3'-nitro-1'-triazole) acetamide (cyclam AK 2123) has been synthesized, radiolabeled and characterized as a hypoxic tumor imaging agent. Radiochemical purity was greater than 95%. Marker biodistribution was measured in normal Wistar strain rats at different time intervals after intra venous (i.v.) administration. In vivo distribution and scintigraphic imaging studies were performed after i.v. injection into mammary tumor-bearing rats using a gamma camera and associated computer. Intratumor partial oxygen pressure (pO2) and oxygen saturation measurements were performed to estimate the oxygenation status of the tumors. Tumor to muscle ratio (T/M) of 99mTc-cyclam AK 2123 was 8.5 which was compared with other tumor seeking radiopharmaceuticals, viz. 99mTc-(V) DMSA (3.07), 99mTc-citrate (5.29) and 201T1C1 (3.29). T/M ratios were also evaluated in comparison with radioiodinated iodoazomycin galactopyronoside (125I-IAZG). The ratio obtained was 18 for 99mTc-cyclam AK 2123 and 20 for 125I-IAZG, respectively. The increased concentration of radioactivity in these tumors suggests that this agent could be labelling hypoxic cells and have utility as an imaging agent.

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Purified field bean protease inhibitor (FBPI) was labeled with 99mTcO4- to ascertain its ability to locate tumors in tumor-bearing rat models. The labeling was done with Sn2+ as a reducing agent and the yield was 95%. It was stable for 2 hr at ambient temperature. The biodistribution study of the intravenously injected radiolabeled FBPI in normal Wistar rats at various time intervals showed a rapid blood clearance from the systemic circulation (approximately 5hr). The complex was predominantly excreted through the renal and the hepatobiliary systems. In vivo distribution and scintiimaging of 99mTc-FBPI were carried out in rats bearing carcinogen-induced mammary tumor or transplanted C6-gliomas. The results obtained were compared with conventional tumor-seeking radiopharmaceuticals such as 99mTc-(V)dimercaptosuccinic acid (DMSA), 201Thallous chloride (TICI) and 99mTc-Citrate. The tumor to muscle (T/M) ratios obtained with 99mTc-FBPI in rat C6 glioma was nearly 2 to 5-fold higher than obtained with all the three conventional tumor-seeking agents. The T/M ratio obtained with 99mTc-FBPI in rat mammary tumor on the other hand appeared to be 2-3-fold higher than noted with 99mTc(V)-DMSA and 201TlCl. The ratio was however comparable with that obtained with 99mTc-Citrate. The study indicated that 99mTc-FBPI has the specific potentials for imaging gliomas and possibly other tumors as well.

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99mTc(V)-DMSA is widely used for imaging medullary carcinoma and hence 186/188Re(V)-DMSA is suggested as a potential agent for treating medullary carcinoma. In the present paper, we report the work carried out for the preparation of [186Re]Re(V)-DMSA and it's bio-distribution studies in Wistar rats. The complex was prepared by reducing 186Re (100 micrograms, 0.54 microM, approximately 150 MBq) in the presence of DMSA (2 mg, 11 microM) with stannous chloride (0.4 mg, 2.2 microM) in acidic medium at pH 2. The reaction was taken to completion by heating the complex in a boiling water bath for 30 min. Bio-distribution studies carried out revealed that pharmacological behaviour of 186Re(V)-DMSA is similar to that of 99mTc(V)-DMSA except that the kidney uptake is marginally higher. The kidney uptake reduced significantly when the pH of the complex was adjusted to 8 prior to injection. The in vitro stability studies of this complex suggest that the product formed is stable and could be used for clinical trials.

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99mTc-HEDP is widely used as a bone imaging agent and its Re analog [186Re]Re-HEDP is now well established as a therapeutic radiopharmaceutical for palliation of pain due to bone metastases. In the present paper, we report the work carried out for the preparation of stable 186Re-HEDP which retains RC purity up to 5 days when stored at 4 degrees C. 186Re was prepared by irradiation of natural Re metal at a flux of 3 x 10(13) neutrons/cm2/s for seven days and processed after a cooling period of four days. The specific activity of 186Re formed was approximately 35 mCi/mg. A complex with RC purity > 98% could be prepared by varying the reaction conditions. By carefully optimizing the reaction and storage conditions, a complex which was stable for over 4 days could be synthesized. Bio-distribution studies carried out in rats revealed approximately 30% bone uptake of 186Re-HEDP at 3 h postinjection which remained almost constant for 48 h, at which time there was negligible activity in other organs.

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Porphyrins, in combination with light, offer an alternate approach to the treatment of cancer, in the form of photodynamic therapy (PDT). With a view to locate new porphyrins for use in PDT, we evaluated the ability of a novel water-soluble porphyrin, meso-tetrakis[4-(carboxymethyleneoxy)phenyl]porphyrin (T4CPP) to induce photodamage in membranes, using rat hepatic microsomes as a model system. Hepatic microsomes treated with T4CPP and exposed to visible light showed significant lipid peroxidation, as assessed by the formation of conjugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances. The peroxidation induced was both time- and concentration-dependent. T4CPP plus light also resulted in the destruction of the microsomal enzymes adenosine triphosphatase and glucose-6-phosphatase. Analysis of the products of peroxidation and selective inhibition by specific inhibitors showed that the oxidative damage induced was mainly due to singlet oxygen and partly due to hydroxyl radical. The porphyrin T4CPP was efficiently labeled with 99mTc. When this 99mTc-labeled porphyrin was injected into a mammary-tumor-bearing rat, it accumulated in the tumor. Our studies suggest that T4CPP, due to its potential to localize in tumors and to induce membrane damage as exemplified by alteration in rat liver microsomes, may have possible applications in this new modality of cancer treatment.

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Human immunoglobulin (HIG) was labelled with 99Tcm using different Sn-ligand (methylene diphosphonate, MDP) in high yields. The effect of Sn:ligand ratios and protein (HIG) on the biodistribution pattern of 99Tcm-HIG in an animal model of turpentine-induced inflammatory lesions was studied. 99Tcm-HIG was excreted predominantly via the renal pathway. The use of higher amounts of MDP and HIG resulted in relatively slower blood clearance and increased uptake of 99Tcm-HIG in various organs. Also, higher amounts of ligand [Sn:MDP (1:5)] resulted in significantly greater bone uptake (P < 0.001), while protein caused slower blood clearance and greater liver uptake. Despite the increased uptake of tracer in various organs, the ratio of inflamed:normal muscle uptake did not change significantly. A scintigraphic study was carried out with both 99Tcm-HIG and 99Tcm labelled with human serum albumin (HSA) in turpentine-induced inflammatory lesions produced in rabbits. The study revealed no significant differences in uptake early on, but the target:non-target ratio was higher with 99Tcm-HIG at 24 h. 99Tcm-HIG also had superior characteristics compared with 99Tcm-HSA.

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Radioiodinated meta-iodobenzylguanidine (131I-MIBG) has been widely used for the diagnosis of neuroblastomas, pheochromocytomas, paragangliomas and medullary carcinomas of thyroid. We have developed a procedure for preparation of 131I-MIBG and studied its utility in diagnosis of primary and metastatic neural crest tumours. Studies were carried out in 54 patients. Of them 39 cases were of neuroblastomas, 1 pheochromocytoma; 6 operated medullary carcinomas; 5 paragangliomas; 2 Ewing's sarcoma and 1 Rhabdomyosarcoma; The sensitivity for the detection of primary tumours of neuroblastomas was 94% and for the detection of metastasis was 83%; while in the case of paragangliomas and medullary carcinoma, the sensitivity was 75% and 70% respectively. Our experience in the present study shows that 131I-MIBG scintigraphy is a sensitive and specific diagnostic tool to localise primary and metastatic disease of neural crest tumours.

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Comparable degree of liver cirrhosis, as judged by liver function tests and histopathology, was induced in rats by carbon tetrachloride. Comparative organ distribution of 99mTc-sulphur colloid and 99mTc-phytate was studied in the liver, spleen and lungs of these cirrhotic rats. Compared to controls, the biodistribution of 99mTc-sulphur colloid was found to be affected more than that of 99mTc-phytate in cirrhotic rats, especially at early time intervals.

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The radiopharmaceutical 99mTc-phytate, formed by reacting the phosphatic ligand, myo-inositol hexakisphosphate with a reduced form of 99mTcO4-, is widely employed in diagnostic nuclear medicine for scinti-imaging the RE system. Despite it being a compound derived from a ligand containing phosphatic functional moieties it does not concentrate to a significant extent in the osseous tissue following i.v. injection into animals or humans. Neither has there been any clinical report citing its localization in the skeletal tissue consequent to its i.v. injection into patients with different types of pathophysiological conditions/metabolic bone disorders. In the course of our study of the homing characteristics of radiopharmaceuticals into specific organ systems or secondary target sites we found that 99mTc-phytate could be directed to some extent into the skeletal tissues of experimental rats by altering its physiological milieu--viz. by decreasing blood calcium levels and increasing bone resorption. Such an altered physiologic condition is obtained by experimentally inducing vitamin D deficiency in animals. Our results show that 8-10% of the administered dose could be redirected to the bone matrix but at the expense of the liver. The study also indicates that many so-called organ specific 99mTc-radiopharmaceuticals could have more than one target tissue/organ system for accumulation consequent to being introduced into the systemic circulation. In a number of instances the secondary target may be masked and may be elicited only under certain specific pathophysiologic conditions.

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The percentage binding of 99Tcm sulphur colloid to blood components (formed elements and plasma proteins) was studied within 1 min of the intravenous injection of the radiopharmaceutical in humans as well as rats. In humans, 68% of the total blood counts were bound to the formed elements (erythrocytes, leucocytes and platelets). The binding pattern (as percentage of plasma counts) among the plasma protein fractions in humans was as follows: albumin, 9.85 +/- 2.06; fibrinogen, 56.70 +/- 7.96; and total proteins, 66.55 +/- 7.32. Activity bound to fibrinogen represented 82.3 +/- 9.1% of the total protein-bound activity in humans. In rats as well fibrinogen was the predominant binding protein (73.8 +/- 5.6). The significant binding of the 99Tcm sulphur colloid to plasma fibrinogen and formed elements of blood may be one of the reasons for the uptake of this radiocolloid in renal transplants before rejection.

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The uptake of 99mTc-MDP, a skeletal radiotracer, was studied at early and late (3 h) time intervals in rats induced with altered thyroid status. Thyroid dysfunction resulted in disturbances in bone mineral metabolism. Rats rendered hypothyroid showed an overall retardation in growth and also considerably reduced skeletal uptake, especially at early time periods. On the other hand, rats rendered hyperthyroid did not show any significant alteration of the skeletal uptake as compared with controls despite enhanced bone turnover normally observed in hyperthyroidism.

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The methodology adopted for the in-house preparation of seven types of "kits" used in the formulation of 99mTc-radiopharmaceuticals, viz. reticuloendothelial, hepatobiliary, renal, skeletal and blood-pool agents, and their control is described. The quality control was performed primarily by following pharmacokinetic patterns (both early vascular "dynamic" and late "static" phases) of the respective radiopharmaceuticals in Wistar strain rats subsequent to i.v. administration of the radiopharmaceuticals. The results obtained could be utilized for quality assurance of 99mTc-radiopharmaceuticals; especially those prepared in-house (from "kits") and use in diagnostic nuclear medicine. The in-house preparation of these "kits" in hospital radiopharmacy laboratories possessing adequate manufacturing facilities, skills and expertise could result in considerable savings in costs (of kits).

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99mTc-phytate, 99mTc-sulfur colloid and 99mTc-antimony sulfide colloid are recognised as RE agents in clinical nuclear medicine. Since these three agents exist in vitro in different forms of particulate aggregation it was of interest to compare their properties and to evaluate the merits and limitations of each of these agents. A comparison was carried out in rats and rabbits as a prelude to a systematic study in human subjects. Quality tested radiopharmaceuticals were prepared and their pharmacokinetics studied in rats. The blood clearance, tissue distribution and scinti-imaging patterns of the RE system were also compared in rabbits. All the agents have excellent localizing properties in the liver but differ in varying extents in their disposition in other tissues. 99mTc-sulfur colloid has some predisposition for the lungs while 99mTc-phytate has a little propensity for the kidney and gut at late time periods. 99mTc-Sb2S3 colloid shows a more pronounced concentration in the bone-marrow, and displays intermediate properties between 99mTc-phytate and 99mTc-sulfur colloid, besides being the most stable (in vitro) radiopharmaceutical in this series of RE agents.

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The effect of induced hypothyroidism (by feeding an antithyroid drug-propylthiouracil) on the transport and clearance of the routinely used hepatobiliary radiopharmaceuticals--radioiodinated iodine-131 (131I) rose bengal and technetium-99m-N-(4-n-butylphenylcarbamoylmethyl) iminodiacetate, was studied in the rats. Hypothyroidism was associated with depressed growth and retarded clearance of these radiotracers from the in vivo system. Treatment of the hypothyroid rats with thyroxine (2-5 micrograms/100 g b.w. day) for 6 wk, restored these parameters towards normal values. These data suggest that delayed clearance of these hepatobiliary tracers could be related to reduced metabolic rate accompanied with the hypotonia and hypomotility of intestine normally observed in the hypothyroid state.

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Eleven different 99mTc compounds having some relevance in clinical nuclear medicine have been classified according to their localizing properties. The following classes of 99mTc compounds have been compared in a semiquantitative manner, using a Wistar strain rat model: liver and hepatobiliary agents such as Tc-phytate, Tc-sulfur colloid, reduced (SnII) TcO-4, and 99mTc-LIDA (dimethyl-IDA); bone agents like Tc-pyrophosphate, Tc-HEDP, Tc-EDTMP; kidney and bladder agents comprising Tc-DTPA, Tc-glucoheptonate, Tc-citrate, and TcO-4. The in vivo pharmacokinetic behavior lends itself to unified approach with respect to nature of 99mTc compounds. Most of the 99mTc complexes display an excretory type of pathway. These compounds were found to be relatively stable in aqueous solutions at room temperature (25 degrees-28 degrees C) for at least 2 h without any additives. Both paper chromatographic and biologic (tissue distribution) criteria, commonly used for quality assurance and control of 99mTc compounds, were employed to study these compounds.

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