Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats

In developing iodine-123-labelled amino acid derivatives for imaging cerebral gliomas by single-photon emission tomography (SPET), we compared p-[¹²³I]iodo-l-phenylalanine (IPA), l-[¹²³I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and l-3-[¹²³I]iodo-!-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T3868 cells, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the ¹²³I-iodinated agents for use as SPET radiopharmaceuticals was evaluated in healthy experimental rats as well as in rats with stereotactically implanted C6 gliomas. The radiopharmaceutical uptake into glioblastoma cells was rapid, temperature and pH dependent, and linear during the first 5 min. Equilibrium was reached after 15-20 min, except in the case of ITIC, the initial uptake of which gradually decreased from 15 min onwards. The radioactivity concentration in glioma cells following 30-min incubation at 37°C (pH 7.4) varied from 11% to 35% of the total activity per million cells (ITIC < IMT h IPA). Competitive inhibition experiments using !-(methylamino)-isobutyric acid and 2-amino-2-norbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transported by system ASC, indicated that IPA, like IMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of the A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analysis of uptake under conditions that change the cell membrane potential, i.e. in high K⁺ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of valinomycin or nigericin induces a slight increase or decrease in the radiopharmaceutical uptake, suggesting a minor contribution of the mitochondria in the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereafter showed efflux from the brain. The radioactivity concentration in healthy rat brain 15 min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactically implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15 min p.i.), with tumour-to-background ratios greater than 4. These data indicate that IPA and ITIC, like IMT, exhibit interesting biological characteristics which hold promise for in vivo brain tumour investigations by SPET.     

Preparation and investigation of tumor affinity, uptake kinetic and transport mechanism of iodine-123-labelled amino acid derivatives in human pancreatic carcinoma and glioblastoma cells

In developing radioiodinated agents for pancreatic and brain tumor imaging by single photon emission tomography (SPET), we prepared p-amino-3-[123I]iodo-l-phenylalanine (IAPA), p-[123I]iodo-l-phenylalanine (IPA), L-8-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyl-tyrosine (IMT) in radiochemical yields up to 95%, and we investigated their uptake in human pancreatic carcinoma and glioblastoma cells as well as the mechanisms promoting the tumor uptake. The radiopharmaceutical uptake into tumor cells was rapid (t(1/2) < or = 5 min) and temperature- and pH-dependent. The radioactivity concentration in tumor cells varied from 10 to 33% of the total activity (105-310 cpm/1000 cells) following a 30-min incubation at 37 degrees C (pH 7.4). In comparison, accumulation of the radiopharmaceuticals into normal brain and pancreatic tissue remained relatively low. Depolarizing the plasma membrane potential in high K+ buffer significantly altered the radioactivity concentration in the tumor cells, suggesting that membrane potential plays a certain role in the cellular uptake. Competitive inhibition experiments with specific amino acid transport inhibitors indicated that the uptake of IAPA, IPA and IMT into human pancreatic carcinoma and glioblastoma cells is predominantly mediated by the L and ASC transport systems, while no substantial involvement of the transport system A in their tumor uptake could be demonstrated. In contrast, results of the present investigation indicated that ITIC is not taken up into tumor cells via the common neutral amino acid carrier systems, including the A, L and ASC system. Furthermore, preloading with naturally occurring L-amino acids failed to stimulate the cellular uptake of the radiopharmaceuticals. These data indicate that the investigated radiopharmaceuticals exhibit interesting characteristics with promise for in vivo tumor investigations to ascertain their potential as radioligands for glioma and pancreatic carcinoma imaging by SPET.     

A strategy for the study of cerebral amino acid transport using iodine-123-labeled amino acid radiopharmaceutical: 3-iodo-alpha-methyl-L-tyrosine

We examined the brain accumulation of iodine-123-iodo-alpha-methyl-L-tyrosine (123I-L-AMT) in mice and rats. I-L-AMT showed high brain accumulation in mice, and in rats; rat brain uptake index exceeded that of 14C-L-tyrosine. The brain uptake index and the brain slice studies indicated the affinity of I-L-AMT for carrier-mediated and stereoselective active transport systems, respectively; both operating across the blood-brain barrier and cell membranes of the brain. The tissue homogenate analysis revealed that most of the accumulated radioactivity belonged to intact I-L-AMT, an indication of its stability. Thus, 123I-L-AMT appears to be a useful radiopharmaceutical for the selective measurement of cerebral amino acid transport.     

Impairment of regional fatty acid uptake in relation to wall motion and thallium-201 uptake in ischaemic but viable myocardium: Assessment with iodine-123-labelled beta-methyl-branched fatty acid

In coronary artery disease, discrepancy in the uptake of thallium-201 and of methyl-branched fatty acid at rest has been described. The purpose of this study was to evaluate iodine-123 labelled beta-methylbranched fatty acid (BMIPP) myocardial uptake and wall motion at rest in segments with stress-induced ischaemia identified by stress²⁰¹Tl tomography in patients with chronic coronary artery disease.¹²³I-BMIPP myocardial tomography was performed at rest and was compared with the findings of exercise-reinjection²⁰¹Tl tomography in 45 patients with chronic coronary artery disease. Regional wall motion was evaluated by contrast left ventriculography in 36 patients. Among 237 segments with reversible²⁰¹Tl defects, equally decreased uptake on both reinjection²⁰¹Tl and BMIPP images was observed in 93 (39%), more severely decreased uptake of BMIPP in 118 (50%) and more severely decreased uptake of reinjection²⁰¹Tl in 26 (11%). On the other hand, among 90 segments with non-reversible²⁰¹Tl defects, each pattern was observed in 71 (79%), 6 (7%) and 13 (14%) segments, respectively. When comparing the ischaemic segments with and without more severely reduced uptake of BMIPP than of reinjection²⁰¹Tl, wall motion was impaired to a greater extent in the segments with more severely reduced uptake of BMIPP than of reinjection²⁰¹Tl [severe hypo- or dyskinesis was present in 64 (70%) of 91 segments and in 24 (22%) of 110 segments, respectively,P<0.005]. In patients with chronic coronary artery disease, resting fatty acid uptake was frequently more reduced than reinjection²⁰¹Tl in the segments with stress-induced ischaemia, while in most of the fixed perfusion defects BMIPP and reinjection²⁰¹Tl uptake decreased concordantly. In ischaemic myocardium, wall motion was impaired to a greater extent in those segments which showed more severely reduced uptake of BMIPP than of reinjection²⁰¹Tl. In ischaemic but viable myocardium, discordant BMIPP uptake less than reinjection²⁰¹Tl uptake may indicate metabolic alterations and wall motion abnormality at rest independent of perfusion abnormalities. In conclusion, the combination of resting BMIPP and stress-reinjection²⁰¹Tl imaging may provide information on metabolic alterations and wall motion abnormality at rest independent of perfusion abnormalities.     

Biodistribution and dosimetry of iodine-123-labelled Z -MIVE: an oestrogen receptor radioligand for breast cancer imaging

This study reports on the distribution and radiation dosimetry of iodine-123-labelled cis-11β-methoxy-17α-iodovinyloestradiol (Z-[¹²³I]MIVE), a promising radioligand for imaging of oestrogen receptors (ERs) in human breast cancer. Whole-body scans were performed up to 24 h after intravenous injection of 138–193 MBq Z-[¹²³I]MIVE in five healthy female volunteers, four with and one without thyroid blockade. Blood samples were taken at various times up to 24 h after injection. Urine was collected up to 24 h after injection in order to calculate renal clearance and to aid in the interpretation of whole-body clearance, including faecal excretion. Time-activity curves were generated for the thyroid, heart, brain, breasts and liver, by fitting the organ-specific geometric mean counts, obtained from regions of interest, to a multicompartmental model. The MIRD formulation, using 11 source organs, was applied to calculate the absorbed radiation doses for various organs upon administration of Z-[¹²³I]MIVE. The images showed rapid hepatobiliary excretion which resulted in good imaging conditions for the thoracic region. Imaging of the abdominal region was impeded due to extensive bowel activity. Diffuse uptake and retention of activity was seen in breast tissue, the breast-to-non-specific uptake ratio increasing over time. Z-[¹²³I]MIVE was cleared by both the kidneys and the gastrointestinal tract. At 50 h p.i. the mean excretion in urine was predicted to be 58%±14% (SD) and that in faeces 31%±19%. If the thyroid was not blocked, it was the most critical organ (0.33 mGy/MBq). In general, the excretory organs received the highest absorbed doses, i.e. the lower and upper large intestinal walls (0.11 and 0.098 mGy/MBq, respectively), the urinary bladder wall (0.090 mGy/MBq), the gallbladder wall (0.087 mGy/MBq) and the small intestine (0.043 mGy/MBq). The average effective dose equivalent of Z-[¹²³I]MIVE was estimated to be 0.033 mSv/MBq. The amount of Z-[¹²³I]MIVE required for adequate breast cancer ER imaging results in an acceptable effective dose equivalent to the patient. Received 28 June and in revised form 26 September 1997     

Iodine-123 α-methyl tyrosine single-photon emission tomography of cerebral gliomas: standardised evaluation of tumour uptake and extent

Single-photon emission tomography (SPET) with the amino acid analogue l-3-[¹²³I]iodo-α-methyl tyrosine (IMT) is helpful in the diagnosis and monitoring of cerebral gliomas. Radiolabelled amino acids seem to reflect tumour infiltration more specifically than conventional methods like magnetic resonance imaging and computed tomography. Automatic tumour delineation based on maximal tumour uptake may cause an overestimation of mean tumour uptake and an underestimation of tumour extension in tumours with circumscribed peaks. The aim of this study was to develop a program for tumour delineation and calculation of mean tumour uptake which takes into account the mean background activity and is thus optimised to the problem of tumour definition in IMT SPET. Using the frequency distribution of pixel intensities of the tomograms a program was developed which automatically detects a reference brain region and draws an isocontour region around the tumour taking into account mean brain radioactivity. Tumour area and tumour/brain ratios were calculated. A three-compartment phantom was simulated to test the program. The program was applied to IMT SPET studies of 20 patients with cerebral gliomas and was compared to the results of manual analysis by three different investigators. Activity ratios and chamber extension of the phantom were correctly calculated by the automatic analysis. A method based on image maxima alone failed to determine chamber extension correctly. Manual region of interest analysis in patient studies resulted in a mean inter-observer standard deviation of 8.7%±6.1% (range 2.7%–25.0%). The mean value of the results of the manual analysis showed a significant correlation to the results of the automatic analysis (r = 0.91, P<0.0001 for the uptake ratio; r = 0.87, P<0.0001 for the tumour area). We conclude that the algorithm proposed simplifies the calculation of uptake ratios and may be used for observer-independent evaluation of IMT SPET studies. Three-dimensional tumour recognition and transfer to co-registered morphological images based on this program may be useful for the planning of surgical and radiation treatment. Received 8 September and in revised form 25 October 1997     

Thyroid uptake and imaging with iodine-123 at 4-5 hours: replacement of the 24-hour iodine-131 standard

A study was carried out to determine the suitability of utilizing a 4 to 5 hr interval from administration of iodine-123 to imaging and uptake measurement as a replacement for the 24-hr standard originally established with iodine-131. In 55 patients who underwent scintigraphy at 4 and 24 hr, there was no discrepancy between paired images. In 55 patients who had uptake measured at 4 and 24 hr and in 191 patients who had uptake measured at 5 and 24 hr, the early measurements proved equal or better discriminants of euthyroid from hyperthyroid patients. In our institutions, these findings and the logistical advantages of completing the exam in 4-5 hr led us to abandon the 24-hr study in the majority of patients.     

The evolution of cerebral blood flow in the developing brain: evaluation with iodine-123 iodoamphetamine SPECT and correlation with MR imaging.

BACKGROUND AND PURPOSE: Although it is well established that brain maturation correlates temporally with the functions the newborn or infant performs at various stages of development, the precise relationship between function and anatomic brain maturation remains unclear. The purpose of this study was to investigate the developmental changes of regional cerebral blood flow (rCBF) in infants and children using iodine-123 iodoamphetamine (123I-IMP) and single-photon emission computed tomography (SPECT). These findings were correlated with the MR imaging appearance of the brain and with known developmental changes. METHODS: Twenty-one 123I-IMP SPECT examinations of 17 patients, ranging in age from neonates to 2 years, were reviewed retrospectively. All children had had transient neurologic events in the neonatal period that did not significantly affect subsequent neuropsychological development. MR studies were performed in 12 of these patients and the MR findings were correlated with the SPECT results. RESULTS: SPECT studies showed a consistent pattern of evolving changes in 123I-IMP uptake, most likely reflecting evolution of rCBF. From the 34th postconceptional week until the end of the second month after term delivery, there was predominant uptake in the thalami, brain stem, and paleocerebellum, with relatively less cortical activity. Radionuclide uptake in both the perirolandic and occipital cortices was well seen around the 40th postconceptional week and increased rapidly thereafter, with a predominance of parietal activity. By 3 months, radionuclide uptake in the cerebellar hemispheres and parietofrontal cortices increased. Frontal and temporal activity increased by age 6 to 8 months. Uptake in the basal ganglia increased by 8 months. By the beginning of the second year, rCBF showed a similar topographic pattern to that in adults. CONCLUSION: The time course of the changes in 123I-IMP uptake in the developing brain as detected by SPECT is similar to that of myelination and most likely reflects an overall topologic maturational pattern of the brain.     

Comparison of iodine-123 epidepride and iodine-123 IBZM for dopamine D2 receptor imaging in clinically non-functioning pituitary macroadenomas and macroprolactinomas

We compared pituitary iodine-123 epide- pride single-photon emission tomography (SPET) and ¹²³I-IBZM SPET for the in vivo imaging of dopamine D₂ receptors in 15 patients with clinically non-functioning pituitary adenomas. Four patients with dopamine agonist-sensitive macroprolactinomas were studied as positive controls. The uptake of radioactivity in the pituitary was established using a visual scoring system and an uptake index calculated by dividing the average count rates in the pituitary area by the average count rates in the cerebellum. All four macroprolactinomas showed specific binding of ¹²³I-epidepride, but only one showed specific binding of ¹²³I-IBZM. Specific binding of ¹²³I-epidepride was demonstrated in 9 of the 15 clinically non-functioning pituitary adenomas (60%), but specific binding of ¹²³I-IBZM was shown in only 6 of these 15 cases (40%). The uptake of ¹²³I-epidepride in the pituitary region was consistently higher than that of ¹²³I-IBZM. None of the patients who showed absence of uptake of ¹²³I-epidepride in the pituitary area showed uptake of ¹²³I-IBZM in this area. In conclusion: ¹²³I-epidepride SPET is superior to ¹²³I-IBZM SPET for the visualization of dopamine receptor-positive pituitary adenomas. Therefore, ¹²³I-epidepride should replace ¹²³I-IBZM for future D₂ receptor SPET studies of pituitary adenomas. ¹²³I-epidepride SPET potentially might serve to predict the response of clinically non-functioning pituitary adenomas to dopamine agonist therapy. Received 11 July and in revised form 25 September 1998     

大鼠C6胶质瘤抗血管生成治疗的MR灌注研究

目的　利用大鼠C6脑胶质瘤模型 ,观察抗血管生成治疗的疗效 ,探讨MR灌注成像在胶质瘤抗血管生成治疗早期疗效评价中的应用价值。方法　SD雄性大鼠 30只 ,右尾状核接种C6胶质瘤细胞复制大鼠脑胶质瘤模型。接种胶质瘤细胞后第 15天 ,分别予以立体定向放射外科治疗 (中心剂量 2 5Gy)和重组人内皮抑制素皮下注射 (5、10和 2 0mg·Kg-1·d-13种剂量 ,共 7d) ,于治疗前和治疗后 4 8h进行MR灌注成像及常规扫描 ,观察肿瘤与正常脑组织的相对脑血流容积 (rCBV)值的改变 ,计算肿瘤体积 ,以肿瘤抑制作为疗效评价的形态学标准。结果　 3种剂量的内皮抑制素治疗结束时肿瘤平均体积分别为 (42 9 0± 36 7)mm3 、(30 5 7± 32 8)mm3 和 (2 77 0± 2 0 6 )mm3 ,立体定向放射外科治疗组第 2 2天时肿瘤体积为 (390 0± 33 8)mm3 ,与对照组 (5 6 6 7± 135 0 )mm3 比较差异均存在显著性意义 (P =0 0 31) ;3种剂量的内皮抑制素治疗后肿瘤的rCBV分别为 1 5 7± 0 12 ,1 30± 0 12和1 2 4± 0 0 8,立体定向放射外科治疗后肿瘤的rCBV为 1 2 3± 0 2 3。各组rCBV和治疗前相比 ,差异均存在显著性意义 (P <0 0 0 1) ,低剂量内皮抑制素治疗组和中、高剂量治疗组相比差异存在显著性意义(P <0 0 0     

3-[123I]Iodo-alpha-methyl-L-tyrosine uptake in cerebral gliomas: relationship to histological grading and prognosis

3-[123I]Iodo-alpha-methyl-L-tyrosine (IMT) is employed clinically as a tracer of amino acid transport in brain tumours using single-photon emission tomography (SPET). This study investigates the role of IMT SPET in the non-invasive histological grading and prognostic evaluation of cerebral gliomas. The files of patients investigated by IMT SPET in our clinic between 1988 and 1996 were evaluated retrospectively. Complete follow-up was available for 58 patients with cerebral gliomas investigated by IMT SPET shortly after tumour diagnosis. Seventeen patients had low-grade gliomas (WHO grade II), 14 had anaplastic gliomas (WHO grade III) and 27 had glioblastomas (WHO grade IV). Thirty-six cases were primary tumours and 22 cases, recurrences. Maximal and mean tumour-to-brain (T/B) ratios of IMT uptake at the first IMT SPET investigation were related to histological grading and survival time. Patients with low-grade gliomas showed significantly longer survival than patients with high-grade (grade III or IV) tumours. Gliomas without contrast enhancement on computed tomography or magnetic resonance imaging scans were associated with longer patient survival than tumours with contrast enhancement. The T/B ratios of IMT SPET showed no differences in relation to histological grading [WHO grade II: 1.73+/-0.59; WHO grade III: 1.74+/-0.38; WHO grade IV: 1.59+/-0.35, (mean+/-SD, T/B ratios of mean tumour uptake)]. The median survival time of patients with a high T/B ratio on IMT SPET was not significantly different from that of patients with a low T/B ratio (T/B ratio <1.6, 14.8 months; T/B ratio > or =1.6, 13.0 months). Thus, no evidence could be found for a relationship between IMT uptake in cerebral gliomas and either histological grading or survival time. Nevertheless, IMT SPET constitutes a useful method for the detection of primary and recurrent gliomas, determination of tumour extent and individual follow-up.     

大鼠C6胶质瘤的MR扩散加权成像及病理对照研究

目的观察大鼠脑C6胶质瘤模型的MR扩散加权成像(DWI)表现,并与肿瘤细胞密度等病理学变化进行对照,分析胶质瘤DWI表现的病理学基础。方法肿瘤细胞接种后12～18d分别对16只肿瘤生长良好的大鼠C6胶质瘤模型进行MR增强及DWI检查,观察胶质瘤MR增强及DWI表现,并与病理学改变进行对照分析。结果7例肿瘤灶增强MRI呈环行强化,表观扩散系数(ADC)图均显示肿瘤中心区域信号明显升高,肿瘤中心与周围区域ADC值分别为[(106.5±11.9)×10-5]、[(78.2±9.2)×10-5]mm2/s,两者之间差异有统计学意义(t=8.26,P<0.01);病理学显示该7只肿瘤灶内部明显坏死,细胞密度明显下降,肿瘤中心及周围区域细胞密度分别为(13±8)%、(40±5)%,两者间差异有统计学意义(t=6.55,P<0.01)。另外9只MR增强扫描肿瘤强化均匀,但其中6只ADC图信号不均匀,中心区及周围区ADC值分别为[(94.1±12.6)×10-5]、[(75.8±11.4)×10-5]mm2/s,两者之间差异有统计学意义(t=5.38,P<0.05)。镜下观察肿瘤中心区域细胞密度下降,肿瘤中心区域及周围区域肿瘤细胞密度分别为(29±4)%、(41±8)%,两者之间差异有统计学意义(t=3.92,P<0.05)。3只ADC图显示信号均匀的肿瘤灶中,其中心区及周围区ADC值分别为[(86.7±9.0)×10-5]、[(84.2±7.6)×10-5]mm2/s,两者之间差异无统计学意义(t=3.41,P>0.05)。镜下肿瘤中心及周围细胞密度分别为(38±7)%、(40±5)%,两者间差异无统计学意义(t=1.92,P>0.05)。结论DWI及ADC的信号差异可以反映胶质瘤内部细胞密度的差异,区别肿瘤内部坏死后的细胞稀疏区和肿瘤增殖旺盛的细胞密集区,为从微观角度观察胶质瘤的结构变化提供了基础。     

Quantitative evaluation of neutral amino acid transport in cerebral gliomas using positron emission tomography and fluorine-18 fluorophenylalanine

To elucidate the mechanism of large neutral amino acid (LNAA) transport in cerebral gliomas and to evaluate the clinical usefulness of positron emission tomography (PET) with fluorine-18 fluorophenylalanine (¹⁸F-Phe), we examined 18 patients with cerebral glioma using dynamic PET and¹⁸F-Phe. By employing two-compartment model analysis, the influx rateK ₁, the efflux ratek ₂ and the distribution volume (V _d) of¹⁸F-Phe were estimated in tumour tissue and contralateral normal grey matter.¹⁸F-Phe showed increased accumulation in tumour tissue regardless of the grade of malignancy in all patients. The rate of uptake of¹⁸F-Phe in high-grade glioma was significantly higher than in low-grade glioma (P <0.05). However, it was difficult to evaluate the tumour grade only from the¹⁸F-Phe accumulation in individual cases. Values ofK ₁ andV _d were significantly increased in the tumour tissue. TheK ₁ value of the tumour tissue tended to decrease with increasing LNAA concentration in plasma. Therefore, influx of¹⁸F-Phe into tumour tissue is mainly related to the carrier-mediated active transport. It is concluded that PET with¹⁸F-Phe is of clinical value for tumour detection rather than assessment of tumour malignancy.     

Kinetics of 3-[(123)I]iodo-l-alpha-methyltyrosine transport in rat C6 glioma cells.

3-[(123)I]Iodo-l-alpha-methyltyrosine ((123)I-IMT) is used for the diagnosis and monitoring of brain tumours by means of single-photon emission tomography (SPET). To date, little has been known about the system for the transport of (123)I-IMT into brain tumour cells. It is assumed that (123)I-IMT is transported by a specific carrier for large, neutral amino acids (L-system). In this study, rat C6 glioma cells were used to characterize the uptake system of (123)I-IMT and to investigate its precise kinetics. The time course of (123)I-IMT uptake into the cells was examined for a range of 1-60 min. (123)I-IMT uptake rates with varying concentrations of (123)I-IMT (2. 5-50 microM) in the medium were quantified to assess the kinetic parameters of (123)I-IMT transport. Furthermore, competition of (123)I-IMT with other amino acids was investigated to identify the distinct transport systems involved in (123)I-IMT uptake. (123)I-IMT uptake into C6 glioma cells was linear for approximately 10 min and reached a steady-state level within 30 min. The analysis of the rate of uptake of (123)I-IMT at different concentrations was concordant with the predominance of a single uptake system. The apparent Michaelis constant (K(m)) of (123)I-IMT was 26.2+/-1.9 microM, and the maximum transport velocity (V(max)) was 35.4+/-1.7 nmol/mg protein per 10 min. 77%+/-10% of (123)I-IMT transport was sodium independent and 23%+/-3% was sodium dependent. Competitive inhibition of (123)I-IMT uptake by 2-aminobicyclo[2.2. 1]heptane-2-carboxylic acid, alpha-(methylamino)isobutyric acid and naturally occurring amino acids revealed a major (123)I-IMT transport via the sodium-independent system L (72%) and a minor uptake via the sodium-dependent system B(0,+) (17%). Our results show that (123)I-IMT transport into C6 glioma cells is principally mediated by the L-system and to a minor extent by the B(0,+)-system. The kinetic parameters of (123)I-IMT uptake are in the range of those of naturally occurring amino acids.     

123I-2-iodo-tyrosine, a new tumour imaging agent: human biodistribution, dosimetry and initial clinical evaluation in glioma patients

Purpose ¹²³I-2-iodo-tyrosine (¹²³I-2IT) has been identified as a promising new amino acid tracer in animals. Uptake is mediated by LAT1 transport, which is increased in tumour cells. In this study we present the human biodistribution and first clinical results in glioma patients. Methods For the biodistribution study, six male volunteers received 60–95 MBq ¹²³I-2IT. Whole-body scans and blood and urine samples were obtained up to 24 h after injection; dosimetry was calculated using OLINDA 1.0 software. Initial clinical evaluation of ¹²³I-2IT SPECT was performed in 35 patients with suspected or known glioma, either as primary diagnosis or for detection of recurrence. Tumour-to-background (T/B) ratios were calculated for semi-quantitative analysis. The results were correlated with clinical and MRI follow-up data or histology. Results ¹²³I-2IT showed both renal and intestinal clearance. Bladder (0.12 mGy/MBq) and small intestine (0.03 mGy/MBq) received the highest absorbed doses. The effective dose equivalent and effective dose were estimated at 0.020 and 0.016 mSv/MBq, respectively. In patients, ¹²³I-2IT SPECT did not differentiate between neoplastic and non-neoplastic lesions after an indeterminate MRI. In follow-up of known glioma, 13/15 patients with disease recurrence had increased T/B values (range 1.39–3.91). Out of seven recurrence-negative patients, two showed an important increase in T/B, in one case due to radionecrosis (T/B 1.59) and in the other probably due to residual but stable disease (T/B 2.07). Conclusion ¹²³I-2IT has a favourable biodistribution for a tumour imaging agent. It shows increased uptake in central nervous system glioma and is potentially useful in the follow-up of glioma patients. M. Keyaerts is an “aspirant” of the FWO-Vlaanderen.     

Scintigraphic evaluation of myocardial ischaemia using a new fatty acid analogue: iodine-123-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA)

Iodine-123-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a branched fatty acid analogue for myocardial imaging, which has been recently designed for medium washout rates from the myocardium. The purpose of this study was to assess the clinical feasibility of use of 9MPA for the evaluation of myocardial ischaemia. Twenty-one patients were injected with 9MPA at rest, and sequential single-photon emission tomography (SPET) acquisitions were performed 5, 45 and 240 min after administration to calculate washout rates from the myocardium. The findings of 9MPA images were analysed in comparison with those of perfusion images with thallium-201 or sestamibi, coronary angiography and left venticulography. In general, reduction of 9MPA uptake was more remarkable than that of perfusion tracers. The findings of 9MPA early images correlated better with those of exercise perfusion images than with the rest images. Measured washout rates of 9MPA from ischaemic myocardium were significantly slower than those from normal myocardium. The majority of areas with abnormal 9MPA distribution manifested wall motion abnormality, while all areas with normal tracer distribution presented normal wall motion. The detectability of myocardial ischaemia was improved by adding mid and delayed images in six cases. However, both washout and fill-in patterns were encountered in ischaemic lesions, rendering the interpretation of images difficult. In conclusion, the results of this study indicated that 9MPA has acceptable myocardial uptake, that its use is feasible for the detection of ischaemia and that the abnormal distribution of the tracer correlates well with wall motion abnormality reflecting metabolic disorders. Received 6 March and in revised form 28 April 1999     

Scintigraphic evaluation of myocardial ischaemia using a new fatty acid analogue: iodine-123-labelled 15-(p-iodophenyl)-9-(R, S)-methylpentadecanoic acid (9MPA).

Iodine-123-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a branched fatty acid analogue for myocardial imaging, which has been recently designed for medium washout rates from the myocardium. The purpose of this study was to assess the clinical feasibility of use of 9MPA for the evaluation of myocardial ischaemia. Twenty-one patients were injected with 9MPA at rest, and sequential single-photon emission tomography (SPET) acquisitions were performed 5, 45 and 240 min after administration to calculate washout rates from the myocardium. The findings of 9MPA images were analysed in comparison with those of perfusion images with thallium-201 or sestamibi, coronary angiography and left venticulography. In general, reduction of 9MPA uptake was more remarkable than that of perfusion tracers. The findings of 9MPA early images correlated better with those of exercise perfusion images than with the rest images. Measured washout rates of 9MPA from ischaemic myocardium were significantly slower than those from normal myocardium. The majority of areas with abnormal 9MPA distribution manifested wall motion abnormality, while all areas with normal tracer distribution presented normal wall motion. The detectability of myocardial ischaemia was improved by adding mid and delayed images in six cases. However, both washout and fill-in patterns were encountered in ischaemic lesions, rendering the interpretation of images difficult. In conclusion, the results of this study indicated that 9MPA has acceptable myocardial uptake, that its use is feasible for the detection of ischaemia and that the abnormal distribution of the tracer correlates well with wall motion abnormality reflecting metabolic disorders.     

In vitro and in vivo evaluation of iodine-123-Ro 16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors

The flumazenil analogue, Ro 16-0154, a benzodiazepine partial inverse agonist, has been labeled by halogen exchange to enable SPECT investigations of central benzodiazepine receptors in the human brain. The purified 123I-Ro 16-0154 was found to be stable in rat brain preparations and to be metabolized in rat liver preparations. Its pharmacologic properties were comparable to those of flumazenil. The biodistribution in rats (1 hr postinjection) resulted in a high brain-to-blood ratio of 16. Clinical studies revealed images of the benzodiazepine receptor density in the brain. Since the receptor labeling was markedly reduced by injection of flumazenil, it was considered to be specific. Storage defects due to pathologic cerebral blood flow and changed receptor density were detected; this shows the potential usefulness of the substance for diagnostic purposes, e.g., the differential diagnosis of various forms of epilepsy.     

In vivo imaging of insulin receptors by PET: preclinical evaluation of iodine-125 and iodine-124 labelled human insulin.

[A(14)-*I]iodoinsulin was prepared for studies to assess the suitability of labeled iodoinsulin for positron emission tomography (PET). Iodine-125 was used to establish the methods and for preliminary studies in rats. Further studies and PET scanning in rats were carried out using iodine-124. Tissue and plasma radioactivity was measured as the uptake index (UI = [cpm x (g tissue)(-1)]/[cpm injected x (g body weight)(-1)]) at 1 to 40 min after intravenous injection of either [A(14)-(125)I]iodoinsulin or [A(14)-(124)I]iodoinsulin. For both radiotracers, initial clearance of radioactivity from plasma was rapid (T(1/2) approximately 1 min), reaching a plateau (UI = 2.8) at approximately 5 min which was maintained for 35 min. Tissue biodistributions of the two radiotracers were comparable; at 10 min after injection, UI for myocardium was 2.4, liver, 4.0, pancreas, 5.4, brain, 0.17, kidney, 22, lung, 2.3, muscle, 0.54 and fat, 0.28. Predosing rats with unlabelled insulin reduced the UI for myocardium (0.95), liver (1.8), pancreas (1.2) and brain (0.08), increased that for kidney (61) but had no effect on that for lung (2.5), muscle (0.50) or fat (0.34). Analysis of radioactivity in plasma demonstrated a decrease of [(125)I]iodoinsulin associated with the appearance of labeled metabolites; the percentage of plasma radioactivity due to [(125)I]iodoinsulin was 40% at 5 min and 10% at 10 min. The heart, liver and kidneys were visualized using [(124)I]iodoinsulin with PET.