Imaging brain tumor proliferative activity with [124I]iododeoxyuridine.

Iododeoxyuridine (IUdR) uptake and retention was imaged by positron emission tomography (PET) at 0-48 min and 24 h after administration of 28.0-64.4 MBq (0.76-1.74 mCi) of [124I]IUdR in 20 patients with brain tumors, including meningiomas and gliomas. The PET images were directly compared with gadolinium contrast-enhanced or T2-weighted magnetic resonance images. Estimates for IUdR-DNA incorporation in tumor tissue (Ki) required pharmacokinetic modeling and fitting of the 0-48 min dynamically acquired data to correct the 24-h image data for residual, nonincorporated radioactivity that did not clear from the tissue during the 24-h period after IUdR injection. Standard uptake values (SUVs) and tumor:brain activity ratios (Tm:Br) were also calculated from the 24-h image data. The Ki, SUV, and Tm/Br values were related to tumor type and grade, tumor labeling index, and survival after the PET scan. The plasma half-life of [124I]IUdR was short (2-3 min), and the arterial plasma input function was similar between patients (48 +/- 12 SUV*min). Plasma clearance of the major radiolabeled metabolite ([124I]iodide) varied somewhat between patients and was markedly prolonged in one patient with renal insufficiency. It was apparent from our analysis that a sizable fraction (15-93%) of residual nonincorporated radioactivity (largely [124I]iodide) remained in the tumors after the 24-h washout period, and this fraction varied between the different tumor groups. Because the SUV and Tm:Br ratio values reflect both IUdR-DNA incorporated and exchangeable nonincorporated radioactivity, any residual nonincorporated radioactivity will amplify their values and distort their significance and interpretation. This was particularly apparent in the meningioma and glioblastoma multiforme groups of tumors. Mean tumor Ki values ranged between 0.5 +/- 0.9 (meningiomas) and 3.9 +/- 2.3 microl/min/g (peak value for glioblastoma multiforme, GBM). Comparable SUV and Tm:Br values at 24 h ranged from 0.13 +/- 0.03 to 0.29 +/- 0.19 and from 2.0 +/- 0.6 to 6.1 +/- 1.5 for meningiomas and peak GBMs, respectively. Thus, the range of values was much greater for Ki (approximately 8-fold) compared with that for SUV (approximately 2.2-fold) and Tm:Br (approximately 3-fold). The expected relationships between Ki, SUV, and Tm:Br and other measures of tumor proliferation (tumor type and grade, labeling index, and patient survival) were observed. However, greater image specificity and significance of the SUV and Tm:Br values would be obtained by achieving greater washout and clearance of the exchangeable fraction of residual (background) radioactivity in the tumors, i.e., by increased hydration and urinary clearance and possibly by imaging later than 24 h after [124I]IUdR administration.

Long-chain F-18 fatty acids for the study of regional metabolism in heart and liver; odd-even effects of metabolism in mice.

In view of the potential usefulness of fluorine-tagged fatty acids in the study of regional metabolism in the heart and liver, the time courses of uptake and release of 9,10-[18F]fluorostearic acid, 2-[18F]fluorostearic acid, 16-[18F]fluorohexadecanoic acid, 17-[18F]fluoroheptadecanoic acid have been investigated in several organs of NMRI mice. Whereas 2-[18F]fluorostearic acid shows very little uptake in the heart muscle but an increasing accumulation in the liver, the fatty acids with the F-18 label in the middle or at the end of the carbon chain exhibit uptake and elimination behavior similar to that of the analogous C-11-labeled compounds. After rapid concentration in the heart within 1 min, clearance takes place with fast and slow components. 16-[18F]fluorohexadecanoic acid and 17-[18F]fluoroheptadecanoic acid have different half-times of elimination. These differences are also reflected by the fact that nearly all the activity present in the heart can be recovered as fluoride(F-18) in the case of 17-[18F]fluoroheptadecanoic acid, whereas practically no fluoride was found among the metabolites of 16-[18F]fluorohexadecanoic acid. Similar differences were observed for the F-18 activity in bone. The results can be interpreted in terms of the odd-even rule: beta oxidation of even-numbered fatty acids ends up with [18F]fluoroacetic acid, whereas the odd-numbered fatty acids give rise to beta-[18F]fluoropropionic acid. Only in the latter case does dehalogenation take place leading to free fluoride, whereas fluoroacetic acid undergoes further reactions in the citric acid cycle.

Radiochemical synthesis of [123I]2-iodo-lisuride for dopamine D2-receptor studies.

By variation of reaction parameters iodination of 3-(9,10-didehydro-6-methyl-8 alpha-ergolinyl)-1,1-diethylurea (lisuride) was performed with the radiohalogen [123I]iodine (t1/2 = 13.3 h). For comparative experiments and stability studies the beta(-)-emitting radioisotope [131I]iodine (t1/2 = 8.04 d) was also used. Reaction occurs at the activated position 2 of the molecule, thus leading to [123I]3-(9,10-didehydro-2-iodo-6-methyl-8 alpha-ergolinyl)-1,1-diethylurea ([123I]2-iodo-lisuride, [123I]ILIS) or the analogous [131I]iodine-labeled compound, respectively. Electrophilic radioactive species were generated by oxidation of no-carrier-added (n.c.a.) iodide with IODOGEN (1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenylglycouril) fixed on the glass wall of the reaction vial prior to iodination. After optimization of reaction parameters [123I]2-iodo-lisuride after HPLC-purification was obtained with radiochemical yields of 70 +/- 5% and a radiochemical purity of > 97%. In n.c.a. syntheses, specific activities of the product were in the range between 4440 and 7400 GBq/mumol (120-200 Ci/mumol) corresponding to 50-85% of the theoretical value.

Radiosynthesis and quality assurance of 5-[124I]Iodo-2'-deoxyuridine for functional PET imaging of cell proliferation.

5-[124I]Iodo-2'-deoxyuridine ([124I]IUdR) was routinely produced by direct electrophilic labelling of 2'-deoxyuridine with 124I of high specific activity (12 Ci/micromol) in an Iodogen-coated ReactiVial, followed by purification on a Sep-Pak C-18 cartridge. The radiochemical purity was determined by TLC on a Silicagel-60 plate and by reverse-phase HPLC on a RP-18 column. Based upon 45 syntheses, the yield ranged from 45% to 65%. The radiochemical impurity of [124I]IUdR was determined at 2.9% by TLC (mainly iodate) and 4.3% by HPLC. The chemical stability of the solvated formulation allowed a time window of 2 days following end of synthesis (EOS) for chemical application, based upon the required 95% radiochemical purity grade of [124I]IUdR. The labelled compound was routinely used for the clinical determination of cell proliferation in glioma patients by positron emission tomography.

Use of 3-fluoro-deoxyglucose for the assessment of cerebral perfusion and glucose transport. I. Theory.

A new model is described applying dynamic positron emission tomography (dPET) and 3-fluoro-deoxyglucose (3FDG) to the measurement of local cerebral perfusion and glucose transport across the blood-brain-barrier (BBB). The model takes advantage of 3FDG being practically not metabolized in brain and being transported back from tissue into the circulation. Simultaneous registration of tracer concentration in blood and tissue by dPET permits the in vivo determination of the Michaelis-Menten constant (K) and maximal velocity (V) for 3FDG and glucose transport across the BBB as well as the determination of local perfusion rate. Values obtained in normal cortex using this method were K = 6.3 mumol/g and V = 2.46 mumol/g min. Local perfusion rate ranged between 0.8 and 0.98 ml/min g.

Use of 3-fluoro-deoxyglucose for the assessment of cerebral perfusion and glucose transport. II. Evaluation of patients undergoing EC-IC bypass surgery.

Dynamic positron emission tomography (dPET) and 3-fluoro-deoxy-glucose (3FDG) have been applied to the followup of selected patients undergoing extracranial-intracranial (EC-IC) bypass surgery. To determine glucose transport across the blood-brain-barrier and local perfusion rate a new mathematical model has been used. Immediately following EC-IC surgery, dPET shows an increase in perfusion of approx. 7 ml/min 100g over both the operated and the contralateral hemispheres indicative of reversal of interhemispheric steal. Followup studies show reduction of local perfusion rate combined with an improvement of glucose transport rates. This finding suggests improvement of cerebral metabolic capacity following improvement of perfusion suggestive of longterm beneficial effects of EC-IC bypass.

Recent developments in the field of 123I-radiopharmaceuticals.

Due to its advantageous nuclear physical properties iodine-123 is an excellent label for radiopharmaceuticals very well suited for measurements by gamma-cameras and single-photon emission tomography. The development of 123I-radiopharmaceuticals should be based on a clear biochemical concept, reliable labelling procedures and careful pharmacokinetic studies in order to evaluate the physiological behaviour of the radioiodinated compounds being analogues of metabolic substrates. The development of 123I-labelled fatty acids and biogenic amines clearly proved the successful use of 123I for labelling compounds applied in medical diagnosis.

[Uptake of DL-3-123I-iodo-alpha-methyltyrosine in recurrent brain tumors]. / Anreicherung von DL-3-123I-Jod-alpha-methyltyrosin in Hirntumorrezidiven.

DL-3-123I-iodo-alpha-methyltyrosine (123I-IMT) is a radiopharmacon which concentrates in brain tumors and can be employed in SPECT. We performed 20 studies in 16 patients after neurosurgery for malignant brain tumors (localization of the primary tumor by CT/MRI). Tumor/non-tumor ratios (T/NT) were calculated in ROI-technique. In 17 cases there was a recurrence or tumor remnant. 14/17 were detectable by increased uptake (T/NT 1.43-2.25). The scans were correlated with CT/MRI studies and validated by biopsy (6/14) or follow-up. All 3 patients without recurrence (neuroradiological follow-up over 6-24 months) had a negative scan. 123I-IMT scintigraphy provides complementary information to CT and MRI. In equivocal neuroradiological or clinical cases it may be valuable in the detection of tumor recurrences and allows an earlier onset of therapy.

[Somatostatin receptor scintigraphy in medullary thyroid carcinomas, GEP and carcinoid tumors]. / Somatostatinrezeptor-szintigraphie bei medullären Schilddrüsenkarzinomen, GEP-Tumoren und Karzinoiden.

For this study, 24 patients with medullary thyroid cancer (MTC) and 10 with carcinoid-/GEP-tumours underwent scintigraphy with 123I-Tyr3-octreotide or 111In-DTPA-D-Phe1-octreotide (Octreoscan) or 99mTc-V-DMSA. Calcitonin and CEA were elevated in MTC patients, the other had tumour lesions on CT. Octreoscan-scintigraphy was positive in 68% of all suspicious cases. On the other hand, 123I-Tyr3-octreotide showed only rarely positive results. 99mTc-V-DMSA-scans in MTC patients were positive in 23%. Liver metastases could be seen only with Octreoscan in the non-MTC-group. These results showed better sensitivity of 111In-labelled octreotide.

Synthesis of, and animal experiments with, N-isopropyl-p-123I-iodo-amphetamine (IMP) and 18F-3-deoxy-3-fluoro-D-glucose (3-FDG) as tracers in brain and heart diagnostic studies.

For the investigation of brain functions 18F-3-deoxy-3-fluoro-D-glucose (3-FDG) and N-isopropyl-p-123I-iodo-amphetamine (IMP) were synthesized and the course of radioactivity measured in several organs of mice. The results can be summarized as follows: IMP is rapidly extracted from the blood and reaches a value of less than 1% g within the first 15 min; 123I-radioactivity in the lungs shows a maximum of 76%/g as soon as half a minute after injection and decreases with a concomitant increase in the liver and brain; The maximum 123I-uptake in the brain of 11%/g is reached after 30 min and levels off at a constant value of 10%/g; 30 min after injection the brain/blood ratio for IMP is about 14; The time course of 3-FDG in the brain has a maximum of 4.8%/g as soon as 5 min after injection and decreases to a constant value of 3%/g within 1 hr; and Accumulation of 18F- radioactivity in the heart reaches a maximum of 14%/g after 1 hr and is eliminated with a half-life of 300 min. Comparative clinical studies with 3-FDG and 3-0-11C-methyl-D-glucose (CMG) have shown that 3-FDG can be considered as a CMG-analogue and thus can be used for the in-vivo determination of local glucose perfusion and transport rates.

Double-nuclide study of the myocardium using 201Tl and 123I-labeled fatty acids in non-ischemic myocardial diseases.

Metabolic impairment and perfusion abnormalities are known to occur in hypertensive heart disease (HHD) and in cardiomyopathies. Free fatty acid (FFA) extraction is severely inhibited in a number of pathobiochemical reactions. This parameter was assessed using the radiolabeled FFA analogue 123I-(p-iodo-phenyl-)-pentadecanoic acid (IPPA) and 201Tl as perfusion marker, both of them injected at maximal physical workload. The regional extraction fraction of IPPA (IPPA-EF) was estimated by relating the regional IPPA and 201Tl uptake to each other. In HHD (normal coronary arteries) with posterior wall thickness less than or equal to 12 mm IPPA-EF was 77 +/- 18% (SD) in septum and 92 +/- 17% in the posterolateral wall (N = 13), with thickness of greater than 12 mm 60 +/- 23% in septum and 61 +/- 20% in the posterolateral wall (N = 8) when compared with IPPA-EF in normal subjects (= 100%, N = 9). In hypertrophic cardiomyopathy (HCM) IPPA-EF averaged 51 +/- 20% in septum and 87 +/- 10% in the posterolateral wall (N = 11). In these patient groups no systematic regional changes in 201TI uptake were observed. In dilated cardiomyopathy (DCM) both IPPA-EF and 201Tl uptake showed distinct regional variations and a great interindividual variability with a mean IPPA-EF reduction of 12% (N = 9). Thus, IPPA uptake in primarily non-ischemic myocardial disease may already be compromised when 201Tl uptake is unchanged. The double-nuclide method for IPPA-EF determination allows to eliminate the influence of flow in FFA imaging and enhances the potential of scintigraphy in the differential diagnosis of HHD versus coronary artery disease.

Relation of myocardial blood flow and initial cardiac uptake of 15-(p-123I-phenyl)-pentadecanoic acid in the canine heart.

In 8 pentobarbital-anesthetized mongrel dogs the correlation between regional myocardial blood flow (RMBF) and regional cardiac uptake of 15-(p-123I-phenyl)-pentadecanoic acid (IPPA) was determined. Three animals were studied under control conditions, in three dogs an acute ischemia was produced by LAD ligation, and two dogs were paced at 195 beats/min. RMBF values were 20-50 ml/min X 100 g in acutely ischemic myocardium. 90-120 ml/min X 100 g under normal conditions and 200-250 ml/min X 100 g during pacing-induced stimulation. Total cardiac uptake of IPPA was 4.5-6% of the injected dose. In normal and acutely ischemic myocardium a good correlation between RMBF and IPPA uptake was obtained. Under stimulated conditions only a moderate increase of IPPA accumulation was found. At RMBF values above 150-170 ml/min X 100 g an upper limit of IPPA uptake was observed and can be explained by limited diffusion or an increased utilization of alternative substrates.

Preparation of 124I solutions after thermodistillation of irradiated 124TeO2 targets.

The 4.15-d radionuclide 124I is produced via the nuclear reaction 124Te(d, 2n) 124I by irradiation of 96% enriched 124TeO2 with 14 MeV deuterons, followed by thermodistillation. In order to minimise the loss of 124I, the quartz distillation tube was fitted to a stainless steel helix capillary trap directly behind the end of the furnace. Using this device, distillation yields of more than 80% were routinely obtained, and the activity was concentrated in markedly less than 100 microL solution. The 124I produced by this method proved to be useful for labelling proteins and IUdR.

Thyroid remnant dose: 124I-PET/CT dosimetric comparison of rhTSH versus thyroid hormone withholding before radioiodine remnant ablation in differentiated thyroid cancer.

AIM: Recombinant human thyroid-stimulating hormone (rhTSH) recently was approved as an alternative to thyroid hormone withholding (THW) to elevate TSH for thyroid remnant ablation in differentiated thyroid carcinoma patients. High ablation success rates are reported with diverse rhTSH-aided (131)I activities. Improved renal function causes approximately 50% faster radioiodine clearance under euthyroidism versus hypothyroidism. Knowledge of comparative remnant radioiodine kinetics, particularly the remnant radiation dose in Gy/GBq of administered (131)I activity (RDpA), could assist in choosing rhTSH-aided ablative activities. MATERIAL AND METHODS: To compare the RDpA, determined through (124)I-positron emission tomography/computed tomography (PET/CT), under the two stimulation methods, we retrospectively divided into two groups 55 consecutive totally-thyroidectomized, radioiodine-naïve patients. The rhTSH group (n=16) received (124)I on thyroid hormone, 24 h after two consecutive daily intramuscular injections of rhTSH, 0.9 mg. The THW group (n=39) received (124)I after weeks-long THW, when serum TSH first measured > or = 25 mIU/L. We performed PET investigations 4 h, 24 h, 48 h, 72 h and 96 h and PET/CT 25 h after (124)I administration. RESULTS: Median stimulated serum thyroglobulin was 15 times higher (p=0.023) and M1 disease almost twice as prevalent (p=0.05) in rhTSH versus THW patients. Mean+/-standard deviation RDpA was statistically equivalent between the groups: rhTSH, 461+/-600 Gy/GBq, THW, 302+/-329 Gy/GBq, two-sided p=0.258. CONCLUSIONS: rhTSH or THW deliver statistically equivalent radiation doses to thyroid remnant and may be chosen based on safety, quality-of-life, convenience and pharmacoeconomic factors. Institutional fixed radioiodine activities formulated for use with THW need not be adjusted for rhTSH-aided ablation.

[123-I-labeled fatty acids for myocardial functional diagnosis]. / 123-J-Markierte Fettsäuren für die Funktionsdiagnostik des Myokards.

For 17-123I-heptadecanoic acid (IHA) and 15-(para-123I-phenyl)-pentadecanoic acid (IPPA) the biochemical and pharmacokinetic results show a physiological behaviour similar to the normally occurring fatty acids. For the nuclear medical application both 123I-fatty acids are very well suited; they are fast and efficiently accumulated in the myocardium and, keeping the patient at rest, they allow to record scintigrams of the myocardium with a quality which is obtained with thallium 201 only under stress conditions of the patient. By sequential registration of the scintigrams time activity curves can be generated reflecting the regional in-vivo turnover of fatty acids in the myocardium. Thus in a non-invasive way it is possible to obtain differential informations of the myocardial function in-vivo.

Radioiodinated fatty acids for cardiological diagnosis.

The development of fatty acids labelled with iodine-123 is reviewed. The variety of methods for producing 123I and introducing radioiodine into the molecule is discussed and the important points of the biochemical background are recalled with the aim of finding a broad application for 123I-labelled fatty acids. The results of the pharmacokinetic studies and biochemical analyses are presented as they prove that both 17-123I-heptadecanoic acid (IHA) and 15-(p-123I-phenyl)pentadecanoic acid (IPPA) exhibit analogous behaviour to that of the naturally occurring fatty acids. Clinical applications demonstrated two fields of importance: applications solely for imaging the heart and assessment of myocardial turnover rates of fatty acids for functional diagnosis. Moreover, very recent studies show that the provision of information about prognosis of myocardial diseases and the applied cardiological therapy appear to be possible.

[Somatostatin receptor scintigraphy. Methodology, indications, results]. / Somatostatinrezeptor-szintigraphie. Methodik, indikationen, ergebnisse.

Somatostatin-receptor scintigraphy has been in clinical use for several years. Most of the experience with somatostatin tumor scintigraphy has been obtained with gastro-enteropathic (GEP) tumors and carcinoids. Clinical applications of somatostatin imaging have been reported in small-cell lung carcinomas, malignant lymphomas, renal-cell carcinomas, breast cancers and medullary thyroid cancers. Somatostatin analogues were initially applicable in larger medical institutions because of the necessity for radioactive labeling with iodine (octreotide to [123I-Tyr3]-octreotide); however, the clinical results with iodinated analogues were worse than the relatively new analogue [111In-DTPA-D-Phe1]octreotide, now available as Octreoscan. This review describes the current status of the clinical application of somatostatin receptor imaging, together with our own experience in carcinoids, GEP tumors and medullary thyroid carcinomas.

Regional myocardial free fatty acid extraction in normal and ischemic myocardium.

The rate constant for free fatty acid influx (k1) was studied in normal and ischemic myocardium. In 15 normal subjects and 30 patients with coronary artery disease, 201Tl and 15-(p-123I-iodophenyl)-pentadecanoic acid (IPPA) were administered during exercise under fasting conditions and at rest. In 10 patients, the study was repeated after percutaneous transluminal coronary angioplasty; in three patients, the study was repeated after infarction. The initial accumulation of IPPA, related to that of 201Tl (both background and crossover corrected), was used for determinations of the regional rate constant of IPPA influx into myocardial tissue (k1*). In normal subjects, no significant differences in k1* between major myocardial segments were found; the average value of k1* was 0.57 +/- 0.13/min (mean +/- SD) at rest and 0.42 +/- 0.06/min at exercise (average workload, 123 +/- 47 W). With increasing free fatty acid plasma concentration and perfusion, free fatty acid influx increased in a saturable fashion. The Michaelis-Menten constant (KM*) and the maximal velocity (Vmax*) for IPPA influx into myocardial tissue were estimated to be 470 nmol/g and 430 nmol/g.min, respectively. In ischemic areas, k1* was reduced to 57 +/- 18% of k1* value in nonaffected segments. The areas were larger than those showing reduced 201Tl uptake. Preinfarction and postinfarction studies showed that the size of 201Tl defects in postinfarction images corresponded with the size of the area with reduced k1* observed in preinfarction scintigrams. Revascularization led to an increase of 201Tl uptake and to normalization of k1*.