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A Phase 2 multicenter trial of 123I-IBF, (S)-5-iodo-7-N-[(1-ethyl-2- pyrrolidinyl)methyl]carboxamido-2,3-dihydrobenzofuran, was conducted to evaluate its clinical efficacy and safety in 158 patients with Parkinson's disease (PD) or Parkinson syndromes (PS). SPECT data were acquired at two hours (2H-SPECT), after intravenous injection of 123I-IBF (167 MBq). Additional SPECT scan at three hours (3H-SPECT) and dynamic SPECT scan at most until one hour were performed when possible. No severe side effects due to 123I-IBF injection were observed. The sensitivity, specificity and accuracy for discriminating PS from PD using the striatal specific binding count-to-frontal cortex count ratio (St/Fc-1) in 3H-SPECT were 72.7%, 81.0% and 78.1% in 64 clinically definite cases (i.e., typical cases), respectively. The putamen-to-caudate ratios were significantly lower in striatonigral degeneration compared with those in PD. The contralateral-to-ipsilateral ratios against the symptomatic side of tremor and/or rigidity in the patients with PD (HoehnYahr I) were significantly higher than the left-to-right ratios in the normal controls. St/Fc-1 in 3H-SPECT was significantly lower in the patients showing a poor response to levodopa than in those showing a good response. The dopamine D2 receptor binding potential (k3/k4), obtained by dynamic SPECT based on compartment model analysis, correlated well with the striatal specific binding count-to-occipital cortex count ratio. These results suggest that 123I-IBF is a promising agent for differential diagnosis and pathophysiological evaluation of PD and PS.

In this age of "Medical Imaging", Nuclear Medicine has occupied a preeminent position, heralded by the following four points: the development of novel radio-nuclides containing compounds (radio-diagnostic and radio-therapeutic agents), the power of extremely sensitive new measuring devices, the highly reliable quantification of physio-pathological changes occurring in disease and the guidance to medical diagnosis. On those four points, Nuclear Medicine will continue to spread, but new frontiers are emerging, and it is challenged to provide measurements of consistently reliable accuracy to guide various forms of treatment and radiotherapy requiring a high standard of competence.

The phase III clinical trial of strontium-89 chloride agent (SMS.2P) was performed in 90 patients with painful bone metastases secondary to prostate (53), breast (18) and other types of cancer (19). Some patients experienced a transient increase in pain or nausea and vomiting. However both symptoms subsided and serious side effects were not observed in any of the patients. As reported, we confirmed some abnormal changes in peripheral blood picture. A decrease in the number of white blood cells and platelets was considered to be partly a result of bone marrow suppression due to 89Sr irradiation. Pain was substantially improved after 89Sr therapy in 58% of the patients and there was some alleviation in 12%. The release from pain was accompanied by an improved quality of life for these patients including sleep patterns and morbidity. Some patients were able to resume their former life styles. Most of the improved patients experienced pain relief from days to one week following 89Sr therapy and in half cases, this remained effective for 2 or 3 months. There were even cases in which the pain relief continued over an observation period of time of clinical study.

Single photon emission computed tomography (SPECT) using 123I-Iomanzenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors, was performed in patients with cerebrovascular diseases (CVD) to determine the clinical signicigance of IMZ SPECT studies in evaluating the pathophysiology of CVD. IMZ SPECT images obtained three hours after administration of the tracer were compared with the images of cerebral blood flow (CBF) studies in 206 cases. In regions with decreased CBF, the uptake of IMZ was relatively preserved in patients with cerebral thrombosis in comparison with cerebral embolism, and in those with perforator branch infarction in comparison with cortical infarction. The uptake of IMZ decreased as a function of both the severity of the decrease in the CBF and the duration of illness in regions with a significantly decreased perfusion reserve. These results suggest that decreased IMZ binding in ischemic stroke reflects the neuronal damage caused by the cerebral ischemia. On the other hand, in patients with intracerebral hemorrhage, the cortical uptake of IMZ was relatively well-preserved in regions with decreased CBF, and the decrease in the uptake of IMZ was more profound as a function of the decrease in the CBF, especially in cases of putaminal hemorrhage. These results also suggest that the decreased cortical CBF is a remote effect caused by a neuronal disconnection, and neuronal damage may occur in regions with severely impaired CBF.

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. The safety and clinical effectiveness of 123I-IMZ SPECT in the diagnosis of brain diseases were evaluated in 655 patients with various brain diseases, such as epilepsy, cerebrovascular diseases, degenerative diseases and mental disorders relating to BZR. This was a Phase 3 study conducted as a multicenter trial at 52 collaborating institutions. There was no significant adverse reactions in the clinical symptoms or abnormal laboratory test values. The investigators judged 123I-IMZ SPECT to be effective in 95% of 638 analyzed cases. The injected dose did not correlate with the image quality or the clinical effectiveness of 123I-IMZ SPECT, suggesting that these items depend largely on the characteristics of the apparatus used, the disease or pathology of the patients, rather than the dose. We conclude that 123I-IMZ imaging is safe and provides effective information based on BZR binding which is useful in the diagnosis of various brain diseases.

A Phase 3 clinical trial of 123I-Iomazenil (IMZ), a tracer which binds specifically to central-type benzodiazepine receptors (BZR), was performed, and the clinical usefulness of IMZ was evaluated in 121 patients with epilepsy (106 cases with partial epilepsy and 15 cases with generalized epilepsy). A regional abnormality in the BZR distribution was detected in late IMZ images in 20 of 24 cases without abnormal MRI and/or X-ray CT findings. Moreover, only 16 of these 20 cases showed abnormal findings in the cerebral blood flow (CBF) images. In partial epilepsy, abnormal regions in late IMZ images agreed or partially agreed with epileptic foci estimated from the clinical symptoms of epileptic seizures, interictal EEG, and MRI and/or X-ray CT findings in 76%, 70% and 96% of the cases detected. These regions also agreed or partially agreed with the estimated epileptic foci in 92% of the cases with foci estimated by combination of those three methods and in 72% of those estimated by ictal EEG. The agreement or partial agreement rates of late IMZ images with each of the other methods were higher than those of CBF images, although the differences were not significant. For surgically-proven epileptic foci without any abnormality in the CBF image, abnormal regions were detected in late IMZ images. These findings suggest that IMZ SPECT is a useful new tool for detecting epileptic foci based on the distribution of BZR in the brain.

Iomazenil (IMZ) is a partial inverse agonist of central-type benzodiazepine receptors (BZR) which binds specifically to BZR with high affinity. A multi-center Phase 3 clinical study was performed to evaluate the clinical usefulness of 123I-IMZ-SPECT in the diagnosis of brain disorders in 169 patients with degenerative neurological diseases and 37 patients with mental disorders such as neurotic, stress-related and somatoform disorders. In dementia, the decrease in activity in late images, obtained three hours after administration of 123I-IMZ, correlated negatively with the dementia score. In Parkinson's disease and spinocerebellar degeneration. 123I-IMZ showed a more profound decrease in uptake in late images than seen in the cerebral blood flow (CBF) images, and this decrease was in proportion to the duration and severity of the illness. In mental disorders, the ratio of the late to early image counts showed a negative correlation with Hamilton's anxiety scale in all regions in the brain cortices. In panic disorders, the ratio of the cerebral count to the cerebellar count in the late images correlated negatively with the severity of the attack in the frontal, temporal and parietal cortices. These results suggest that 123I-IMZ-SPECT enables us to evaluate the neuronal damage in degenerative diseases and the decrease in the BZR binding potential in mental disorders.

A phase 2 study of 123I-Iomazenil (IMZ) was performed to evaluate its clinical usefulness in SPECT imaging of central-type benzodiazepine receptors (BZR). A total of 246 patients with various central nervous system disorders [82 with epilepsy, 94 with cerebrovascular disease (CVD), 47 with degenerative disorders, 14 with mental disorders relating to BZR and 9 with other diseases] were intravenously injected with 111-222 MBq of IMZ. Early and late images were obtained 15 min and 180 min after injection as the mid-scan time, respectively. In comparison with regional cerebral blood flow (rCBF) images, the uptake of IMZ in the late images, which reflect the regional distribution of BZR, was relatively preserved compared to the uptake of CBF tracers in most of the patients with CVD. In the area of hyperperfusion in the subacute phase of cerebral infarction, however, the defects of IMZ uptake were accompanied by increased uptake of the CBF tracers. On the other hand, late IMZ uptake in most of the patients with the other diseases was decreased more significantly than the uptake of the CBF tracers, suggesting that cortical neuronal damage is more prominent than rCBF in these diseases compared to the vascular perfusional state. No adverse reactions were recognized relating to the IMZ administration. These results suggest that IMZ may provide us with valuable information for assessing pathophysiological state in the brain, which are difficult to achieve with other imaging modalities.

A phase 2 clinical study of 123I-iomazenil (IMZ) was performed to evaluate its clinical usefulness as central-type benzodiazepine receptor imaging agent in 81 cases with epilepsy, 82 cases with cerebrovascular diseases (CVD), 35 cases with degenerative disorders and 14 cases with mental disorders. In epilepsy, IMZ SPECT images for detection of epileptic foci showed relatively high specificity compared with EEG recording in not only interictal but also ictal state, in spite of the fact that IMZ SPECT images was performed during interictally. It was surmised that IMZ SPECT provides valuable clinical information for detection of epileptic foci which are hard to be diagnosed by EEG. The frequency of abnormal findings by IMZ late images was higher than that by interictal blood flow images and comparable to that by ictal blood flow images. In patients with CVD, different observations were obtained between IMZ late images and blood flow images; for example, in regions of hemodynamic cerebral ischemia, postischemic reperfusion and other pathological perfusion, IMZ late images seemed to reflect the degree of cortical neuronal loss. In patients with degenerative disorders, the binding potential (calculated by a simple quantitative method for IMZ) and other parameters correlated with the dementia score. While the number of examined cases with mental disorders was limited, the frequency of abnormal findings with IMZ imaging was higher than that with morphological imaging.

The biodistribution, metabolism and excretion of 123I-iomazenil have been studied in rats, rabbits and humans following i.v. administration. In all the species, 123I-iomazenil was rapidly metabolized and more than 90% of the administrated radioactivity was excreted within the first 24 hr. Dominant metabolites were acid metabolite (R-COOH), glucuronide of the acid (R-COOH-Glc) and free iodide (I-) in rats and humans. On the other hand, R-COOH, oxidative metabolite (R'-CH2COOH) and I- were found in rabbits. Thus, the possible metabolic pathways of iomazenil were hydrolysis, oxidation, conjugation and deiodination. The radioactivity was excreted into both urine and feces in rats, while primary route of excretion in rabbits and humans was from the kidneys. At 3 hr after injection, more than 97% of the radioactivity in rat brain was found in the form of the parent compound. This result indicates that metabolites of 123I-iomazenil do not cross the blood-brain barrier.

A Phase 1 clinical study of 123I-iomazenil (IMZ), a new radiopharmaceutical developed for evaluation of central-type benzodiazepine receptor (BZR) with SPECT, was performed to examine its safety and biodistribution in six healthy volunteers. The brain uptake of 123I-IMZ reached a maximum value of 11.7 +/- 1.6% of the injected dose at 10-20 min after i.v. administration, and then decreased slowly. The regional tracer distribution immediately after injection (0-10 min) was considered to be a reflection of the cerebral blood flow. From 2 to 3 hours post-injection, washout of the radioactivity from the deep gray matter was observed, resulting in the distribution reflecting the reported distribution of BZR. No significant accumulation was seen in any organ other than the brain. The estimated absorbed dose of 123I-IMZ calculated by the MIRD method was comparable to that of 123I-N-isopropyl-p-iodoamphetamine. Neither adverse reactions nor abnormal clinical laboratory findings due to the drug administration were observed. These results suggest that 123I-IMZ is a safe and promising agent for evaluating the function of central-type BZR.

A Phase 3 clinical study of 99mTc-mercaptoacetyl glycylglycylglycine (99mTc-MAG3) injectable was performed in 506 patients with renal and/or urinary disorders. The scintigraphic findings and renogram patterns of 99mTc-MAG3 were similar to those of 123I-OIH, and Tmax and T1/2 of the 99mTc-MAG3 renogram correlated with those of 123I-OIH (r = 0.62 and r = 0.74, respectively). The clinical efficacy of 99mTc-MAG3, evaluated by the investigators in the same patients, was superior to the efficacy of 123I-OIH and 99mTc-DTPA in 93 of 150 patients (62.0%) and 68 of 151 patients (45%), respectively. The image quality and the reliability of the scintigraphic findings with 99mTc-MAG3 were superior to those with 123I-OIH and 99mTc-DTPA, which reflect the more abundant photons of 99mTc-MAG3 than those of 123I-OIH and higher renal extraction of 99mTc-MAG3 than those of 99mTc-DTPA, respectively. Neither adverse reactions nor abnormal laboratory findings due to 99mTc-MAG3 administration were observed. These results suggest that 99mTc-MAG3 injectable is safe and a useful radiopharmaceutical for diagnosis of renal and urinary disorders.

The clinical usefulness of scintigraphy with thallium-201 (201Tl) chloride injection was evaluated in 79 patients with suspected bone, soft tissue or mediastinal tumors. No abnormal changes of subjective or objective signs and clinical test values were observed post injection. It is considered that 201Tl chloride is a safe radiopharmaceutical. In comparison with benign tumors, malignant tumors showed longer retention or more increased uptake of the 201Tl in the lesions on delayed images. The results suggested that the evaluation of changes of 201Tl uptake might be useful to some extent to differentiate malignant tumor from benign tumor. It is considered that 201Tl scintigraphy is useful for evaluating the location and extent of tumor and differentiating malignant from benign tumor.

Forty-eight patients with suspected brain tumor were studied to evaluate the clinical efficacy of Thallium-201 (201Tl) SPECT. 201Tl scintigrams showed abnormal accumulation in 24/26 (92.3%) and 9/14 (64.3%) of patients with malignant and benign tumors, respectively. 201Tl tended to be retained more prominently in malignant brain tumors than in benign ones. The lesion-to-normal ratios (L/N ratios) of 201Tl demonstrated significant correlation with those of 18F-FDG (n = 5, r = 0.90, p = 0.044). L/N ratios were higher in patients with recurrent tumors than those with necrotic lesions (3.33 +/- 0.81 and 1.73 +/- 0.81, respectively, p = 0.0123). The positive predictive value of L/N ratiosor = 2.5 for diagnosing as recurrence and L/N ratios2.5 as necrosis were 83.3% and 100%, respectively. These results suggest that 201Tl scintigraphy may be useful to determine the malignancy of brain tumors and to differentiate recurrence from necrosis after therapeutic procedures.

Clinical utility for detection of hyperfunctioning parathyroid glands in patients with primary and secondary hyperparathyroidism (PHPT, SHPT) using 201TlCl and 99mTcO4-images was estimated in 50 patients including 18 PHPT and 32 SHPT (male; n = 31, female; n = 19, 51.5 +/- 11.1 yr). Detection of 94 hyperfunctioning parathyroid glands in 34 cases were achieved correctly by 201TlCl and 99mTcO4- images in agreement with surgical findings. Detectability of hyperfunctioning parathyroid glands was 100% in more than 1.0 g, 62.0% in more than 0.5 g and 41.5% in less than 0.5 g respectively. Ectopic parathyroid glands in two cases and a metastasis to pretracheal lymph node in one case were clearly demonstrated. Our results show that parathyroid scintigraphy using 201TlCl and 99mTcO4- as well as 131I or 123I is useful and safe method for preoperative detection of hyperfunctioning parathyroid glands.

A phase 2 clinical study of 99mTc-mercapto acetyl glycylglycylglycine (99mTc-MAG3) injectable, a new dynamic renal imaging agent, was performed in 110 patients with renal and/or urinary disorders to evaluate the safety, efficacy and optimal dose of this agent. Neither adverse reactions nor abnormal laboratory findings due to intravenous administration of 99mTc-MAG3 were observed. The investigators evaluated the clinical efficacy of 99mTc-MAG3 was to be effective in 96 of 97 cases. Among the doses of 92.5 MBq, 185 MBq, 370 MBq and 555 MBq, the dose of 92.5 MBq was not large enough to provide adequate-quality blood flow images or reliable information for evaluation of the renal blood flow. It was concluded that the optimal dose range of 99mTc-MAG3 was 185-555 MBq with 370 MBq as the standard dose. Also, we surmise that 555 MBq is especially recommendable when detailed blood flow information is required. These results indicate that 99mTc-MAG3 injectable is useful for the diagnosis of renal and urinary disorders.

A multicenter clinical trial of 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3), a new 99mTc-labeled renal scintigraphic and renographic dynamic functional agent, was performed to evaluate its clinical usefulness at 24 hospitals. The study was performed as a phase III clinical trial and total 357 patients with renal or urinary disorders were examined. There was no adverse reactions in all patients therefore administration agent was judged to be safe by the investigators. 99mTc-MAG3 was proved and concluded to have a superior effectiveness by the investigators in all 347 patients, and by the committee composed of eight representative investigators in 346 patients (99.7%). 99mTc-MAG3 gives a good quality of images of renal, perfusion phase and function-excretory phase as well as functional informations in comparison with 123I-OIH. The committee decided that 99mTc-MAG3 had a superior effectiveness than 123I-OIH in 147 out of 153 cases (96.1%). It is concluded that 99mTc-MAG3 is a safe and effective radiopharmaceutical for routine use in diagnosis of renal dynamic function.

A phase 3 clinical study of a newly developed brain perfusion agent, 99mTc-L,L-ethyl cysteinate dimer (99mTc-ECD), was performed in 521 cases of cerebrovascular diseases and impairment of brain function to evaluate the safety, effectiveness and usefulness of the agent as a multi-center study involving 35 institutions in Japan. Out of 510 cases evaluated for the clinical usefulness, valuable information for clinical diagnosis was obtained in 486 cases (95.3%), and 444 cases (87.1%) were judged as "extremely useful" or "useful". Although the positive ratio of abnormalities detected by the agent was as same as that of 99mTc-hexamethylpropyleneamine oxime (99mTc-HM-PAO), the abnormal regions detected by the agent had tendency to be larger in size and to have higher contrast than those detected by 99mTc-HM-PAO. It is concluded that 99mTc-ECD is a safe and useful radiopharmaceutical as a brain perfusion agent for the diagnosis of cerebrovascular diseases and impairment of brain function.

A phase I study was performed in three normal volunteers to evaluate the safety and biodistribution of 99mTc-MAG3 which was developed as a renal scintigraphic and renographic dynamic function agent. There was no significant adverse reaction, change in vital signs and clinical laboratory data by the injection of 99mTc-MAG3. Therefore it is assumed that the safety of the agent is high. Clearance of injected 99mTc-MAG3 from blood was rapid and the agent was excreted into urine. Immediately after administration of the agent, renal dynamic scintigraphy was performed and provided better quality of images and renograms. Peak time in the renogram was about 3 min post injection and residual count rate to the peak count at 20 min after injection was 19.3%. Cumulative urinary excretion during the first 30 min and 3 hr expressed in %Dose was 77.1 +/- 3.5% and 94.1 +/- 2.7%, respectively. Radiation dose estimates calculated with MIRD method, in the highest organ, bladder, is 5.78 mGy/200 MBq, which seems to be within permissible range for routine examination in nuclear medicine. It is concluded that 99mTc-MAG3 is a safe and promising radiopharmaceutical in diagnosis of renal dynamic function.

We analyzed metabolites of 123I-BMIPP in blood and urine using rats, rabbits and human, while human samples were obtained from normal volunteers of Phase I clinical study. We estimated metabolic pathway of 123I-BMIPP as a myocardial metabolic imaging agent. Radioactivity accumulated in heart after administration gradually decreased and was mainly excreted to bladder via kidneys. The main radioactive component in blood was 123I-PIPA for any species and the urinary components were metabolic conjugates of 123I-PIPA. As results of these studies, we considered that 123I-BMIPP was metabolized to 123I-PIPA by alpha-oxidation process for the first step, follow by beta-oxidation process, then 123I-PIPA was released to blood from tissues. Moreover, 123I-PIPA in blood was conjugated with other compounds and excreted to the bladder.

A phase 2 clinical study of a newly developed brain perfusion agent, 99mTc-ECD, was performed in 166 cases of cerebrovascular diseases and impairment of brain function to evaluate effectiveness, usefulness, optimum dose and optimum timing of imaging as a multi-center study involving 10 institutions in Japan. All cases were judged as no problems on safety and any side effects due to the administration of the compound were not observed. Out of 163 cases evaluated for the clinical usefulness, valuable information for clinical diagnosis was obtained in 160 cases (98.3%), and 154 cases (94.5%) were judged as "extremely useful" or "useful". Although SPECT imaging was possible from 5 min after injection, images obtained between 60 and 90 min after injection showed relatively better image quality in many cases. Regarding standard administration dose, 400 to 800 MBq were considered to be appropriate. 99mTc-ECD is considered to be a promising radiopharmaceutical as a brain perfusion agent.

A phase I clinical study of 99mTc-L,L-ethyl cysteinate dimer (99mTc-ECD) was carried out in 3 normal volunteers. There was no significant change in vital signs and laboratory parameters attributing to the radiopharmaceutical. 99mTc-ECD was rapidly taken up by the brain, reaching the maximum peak activity within 1 min after the injection and remained relatively constant over several hours. The brain uptake of 99mTc-ECD at 5 min was 5.4 +/- 0.5% which decreased to 5.0 +/- 0.3% by 65 min. 99mTc-ECD cleared rapidly from other organs. The primary excretion route was through the kidneys. Cumulative 99mTc activity in the urine at 90 min and 24 hr were 60.2 +/- 7.3% and 88.5 +/- 10.3%, respectively. The critical organ was the bladder wall with an estimated radiation dose of 0.073 mGy/MBq, which was acceptable value. Clear SPECT images were obtained at 30, 90 and 150 min postinjection. In conclusion, 99mTc-ECD is a safe and promising radiopharmaceutical for the evaluation of regional cerebral blood flow.

A multi-center trial of beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid (123I-BMIPP) was performed to assess its clinical usefulness in the evaluation of myocardial fatty acid metabolism in 587 patients with various heart diseases. 123I-BMIPP showed relatively decreased uptake compared with 201Tl in the myocardial lesions of 62% of patients with ischemic heart disease (IHD), 39% of those with cardiomyopathy and 32% of those with other heart diseases. In case of myocardial infarction, less uptake of 123I-BMIPP (Type B) than 201Tl was more frequently seen in patients with successful recanalization than in those without recanalization. The patients with matched distribution of the two tracers (Type E) increased in the direct proportion to the interval between the onset of myocardial infarction and the radionuclide studies. The uptake of 123I-BMIPP correlated well with myocardial viability evaluated by 201Tl exercise-redistribution studies. Type B was frequently seen in the areas with 201Tl redistribution, while Type E was seen in the fixed defect areas. In the other heart diseases studied, Type E was observed in approximately 60% of patients with dilated or secondary cardiomyopathies. Type B was seen in about 45% of patients with valvular heart diseases and myocarditis. Various types of mismatch between the two tracers were demonstrated in hypertrophic cardiomyopathy and hypertensive heart disease. It is concluded that 123I-BMIPP is a safe and useful agent for the diagnosis of various heart diseases, since it reflects myocardial fatty acid metabolism.

A phase 2 study of beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid (123I-BMIPP), a myocardial imaging agent developed for evaluating myocardial fatty acid metabolism, was performed in 197 patients with various heart diseases. The myocardial distribution of 123I-BMIPP did not change from early to late images in 88% of 91 patients with ischemic heart disease (IHD), while washout and/or fill-in were observed in 45% of 55 patients with hypertrophic cardiomyopathy (HCM). In comparison with 201Tl in 165 patients with various heart diseases, the decrease in uptake was more profound with BMIPP in 56% and with 201Tl in only 4%. 123I-BMIPP showed more severely decreased uptake in 83% of the patients with subacute myocardial infarction (15 to 30 days after the onset) and in 73% of the patients with HCM. High-quality SPECT images were obtained with 123I-BMIPP in 93% of 194 patients analyzed. However, the image quality in cardiomyopathy was inferior to that in IHD. The optimal injection dose range and standard dose of 123I-BMIPP were considered to be 74-148 MBq and 111 MBq, respectively. These findings suggest that 123I-BMIPP myocardial imaging is safe and useful for evaluating myocardial fatty acid metabolism in various heart diseases.

A multi-center clinical study was performed in patients with hepatic disorders to evaluate the clinical usefulness of 99mTc-DTPA-galactosyl serum albumin (99mTc-GSA), a new radiopharmaceutical which binds to asialoglycoprotein receptors on hepatocytes. The blood clearance and hepatic accumulation were evaluated on the basis of the dynamic data and serial hepatic images obtained for 20 min after 99mTc-GSA injection. The blood clearance and hepatic accumulation indices of 99mTc-GSA demonstrated the followings. 1) In acute liver diseases, these indices reflected the clinical features of the disease and correlated with the laboratory test indices for the blood coagulation system. 2) In chronic liver diseases, these indices changed in direct proportion to the progression of the hepatic disorder and correlated well with the conventional laboratory test results. 3) In obstructive jaundice, these indices aided evaluation of the liver function despite the high serum bilirubin level. 4) The indices reflected the change in the number of hepatocytes before and after hepatectomy. The scintigraphic findings with 99mTc-GSA permitted both functional and morphological evaluations of the liver and provide additional information compared with conventional liver scintigraphy. These results suggest that 99mTc-GSA scintigraphy may be useful for evaluating both the function and morphology of the liver from a new viewpoint of receptor-mediated accumulation.

Phase II study of 99mTc-DTPA-galactosyl human serum albumin (99mTc-GSA), a new radiopharmaceutical which binds to the asialoglycoprotein receptors on the hepatocytes, was performed in 81 patients with liver diseases to validate its safety and possibility for the evaluation of hepatic function. None of adverse reactions, abnormal clinical laboratory findings and anti-99mTc-GSA antibody production due to 99mTc-GSA was recognized. Immediately after the injection of 99mTc-GSA, the dynamic data and serial hepatic images were obtained for 60 min. The indices for blood clearance and liver accumulation were calculated based on the counts in the regions of interest on the hearts and livers. In 54 patients with chronic hepatic disorders such as liver cirrhosis, the blood clearance and liver accumulation of 99mTc-GSA were retarded according to the progress of the hepatic disorders. The findings of 99mTc-GSA scintigraphy also reflected the hepatic functions of the patients with large hepatic tumors, obstructive jaundice and acute hepatitis. These results suggest that 99mTc-GSA has the clinical potentials to evaluate the liver functions in the patients with hepatic disorders.

Multicenter Phase III clinical trial on a new myocardial imaging agent, 99mTc-hexakis 2-methoxy isobutyl isonitrile (99mTc-MIBI), was carried out in 464 patients with various cardiac disorders. Both planar and tomographic images provided high-quality regional myocardial perfusion images which correlated well with 201TlCl images. The positive ratios of myocardial infarction and angina pectoris by the agent were as high as that of 201TlCl. In addition, ventricular function and wall motion could be assessed with first-pass and ECG gated studies. There was no serious adverse reaction which were attributed to 99mTc-MIBI in any of patients studied. A transient metallic taste was observed immediately after the injection in approximately 64% of the patients. Based on its safety and efficacy, the clinical usefulness of 99mTc-MIBI was observed in 562 (93.1%) of 604 injections. In conclusion, 99mTc-MIBI was useful as a imaging agent of myocardial blood flow.

Technetium-99m-DTPA-galactosyl human serum albumin (99mTc-GSA) is a new radiopharmaceutical which binds to the asialoglycoprotein receptors located specifically on the hepatocytes. Phase I study of 99mTc-GSA was performed on seven normal volunteers, who were intravenously injected with 185 MBq (5 mCi) and 1-10 mg of 99mTc-GSA. None of adverse reactions, abnormal findings of laboratory test and anti-99mTc-GSA antibody production was recognized. The livers were clearly visualized in all subjects. In the pharmacokinetic analyses on five subjects, 99mTc-GSA was rapidly taken up by the livers immediately after the injection and was slowly excreted through the biliary tracts and the urinary tracts. Dose-dependency which is a specific feature for the receptor-mediated agents was observed; the blood clearances of 99mTc-GSA were prolonged in proportion to the injected ligand doses. These results suggest that 99mTc-GSA may be a potential agent for evaluating hepatic functions based on the hepatic receptor quantities.

A phase I clinical study on 99mTc-hexakis 2-methoxy isobutylisonitrile (99mTc-MIBI) was carried out in 6 normal volunteers. There was no significant change in vital signs and laboratory parameters attributing to the reagent other than complaint of slight and transient metallic taste immediately after the injection in 4 volunteers. The highest dosimetry was calculated as 1.1 mGy/37 MBq at lower large intestine, which was within the acceptable range. 99mTc-MIBI was rapidly cleared from the blood and accumulated in the heart immediately after the injection with 1.4% dose and 1.8% dose at 5 min at rest and at stress, respectively. The retention of radioactivity in the heart well continued for at least several hours. The heart-to-lung ratio was over 2.00 at 5 min and heart-to-liver ratio was over 1.00 at 60 min. Myocardial planar and SPECT images were obtained with high quality. In conclusion, 99mTc-MIBI is a useful myocardial perfusion imaging agent.

Phase 1 study of beta-methyl-p-(123I)-iodophenylpentadecanoic acid (123I-BMIPP), a new radiopharmaceutical developed for the evaluation of myocardial fatty acid metabolism, was performed in six normal volunteers to evaluate its biodistribution and safety. After intravenous injection of 111 MBq of 123I-BMIPP, the agent accumulated to the myocardium rapidly (5.4 +/- 0.6% at 1.5 hr after injection) and was washed-out slowly (5.1 +/- 0.4% at 3.0hr). 123I-BMIPP demonstrated no significant accumulation to any specific organs other than myocardium, liver and muscle. Myocardium was clearly visualized in the planar and SPECT images obtained 30 min and 3 hrs after injection. The absorption doses from 123I-BMIPP estimated by MIRD method were lower than those from 201Tl in all organs. Neither adverse reactions nor abnormal clinical laboratory findings were found in the safety evaluation. These results suggest 123I-BMIPP is a promising agent for evaluating myocardial fatty acid metabolism.