Human biodistribution and dosimetry of [123I]FP-CIT: a potent radioligand for imaging of dopamine transporters

This study reports on the biodistribution and radiation dosimetry of iodine-123-labelled N-ω-(flu- oropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([¹²³I]FP-CIT), a promising radioligand for the imaging of dopamine transporters. In 12 healthy volunteers, conjugate whole-body scans were performed up to 48 h following intravenous injection of approximately 100 MBq [¹²³I]FP-CIT. Attenuation correction was performed using a transmission whole-body scan obtained prior to injection of the radioligand, employing a ¹²³I flood source. Blood samples were taken and urine was freely collected up to 48 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, striatum, lungs and liver were fitted to a multicompartmental model to give time-activity curves. The cumulative urine activity curve was used to model the urinary excretion rate and, indirectly, to predict faecal excretion. Using the MIRD method, nine source organs were considered in estimating absorbed radiation doses for organs of the body. The images showed rapid lung uptake and hepatobiliary excretion. Diffuse uptake and retention of activity was seen in the brain, especially in the striatum. At 48 h following the injection of [¹²³I]FP-CIT, mean measured urine excretion was 60%±9% (SD), and mean predicted excretion in faeces was 14%±1%. In general, the striatum received the highest absorbed dose (average 0.23 mGy/MBq), followed by the urinary bladder wall (average 0.054 mGy/MBq) and lungs (average 0.043 mGy/MBq). The average effective dose equivalent of [¹²³I]FP-CIT was estimated to be 0.024 mSv/MBq. The amount of [¹²³I]FP-CIT required for adequate dopamine transporter imaging results in an acceptable effective dose equivalent to the patient. Received 14 July 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     

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     

Biodistribution and dosimetry of (iodine-123)-iodomethyl-N,N-diethyltamoxifen, an (anti)oestrogen receptor radioligand

This study reports on the distribution and radiation dosimetry of iodine-123 labelled trans-Z-iodomethyl-N,N-diethyltamoxifen (123-ITX), a promising radioligand for prediction of the therapeutic efficacy of unlabelled tamoxifen in human breast carcinoma. Whole-body scans were performed up to 24 h after intravenous injection of 123-ITX (mean: 146 MBq, range: 142–148 MBq) in five female volunteers, four with and one without thyroid blockade. Blood samples were taken at various times up to 24 h after injection. Urine was also collected up to 24 h after injection, allowing calculation of renal clearance and interpretation of whole-body clearance. Time-activity curves were generated for the thyroid, heart, brain, breasts, liver and gallbladder by fitting the organ-specific geometric mean counts, obtained from regions of interest. The MIRD formulation was applied to calculate the absorbed radiation doses for various organs. The images showed rapid hepatobiliary excretion, resulting in good imaging conditions for the thoracic region, whereas imaging of the abdominal region was impeded by extensive bowel activity. The breast to non-specific uptake ratio increased over time. 123-ITX was cleared by both the kidneys and the gastrointestinal tract. At 50 h p.i. the mean excretion in the urine was 89.4% (SD 5.7%). If the thyroid was not blocked, it was one of the critical organs. The highest absorbed doses were received by the excretory organs, i.e. the urinary bladder wall, the lower and upper large intestine, and the gallbladder wall. The average effective dose of 123-ITX was estimated to be 0.0084 mSv/MBq. The amount of 123-ITX required for adequate imaging of tumoral uptake results in an acceptable effective dose to the patient. Received 18 February and in revised form 29 April 1999     

Pharmacokinetics and dosimetry of iodine-123 labelled PE2I in humans, a radioligand for dopamine transporter imaging

The iodine-123 labelled selective ligand N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl)nortropane ([¹²³I]PE2I) was evaluated as a probe for in vivo dopamine transporter imaging in the human brain. Six healthy subjects were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 1 h after injection. The background radioactivity was low. The volume of distribution in the striatum was 94±24 ml/ml. The results were compared with those of [¹²³I]β-CIT imaging. There was no significant uptake of [¹²³I]PE2I in serotonin-rich regions such as the midbrain, hypothalamus and anterior gingulus, suggesting that in vivo binding is specific for the dopamine transporter. One main polar metabolite of [¹²³I]PE2I was found in plasma, and the parent plasma concentration decayed rapidly. Radiation exposure to the study subject is 0.022±0.004 mSv/MBq (effective dose). The preliminary results suggest that [¹²³I]PE2I is a selective SPET ligand for imaging striatal dopamine transporter density. Received 9 December 1997 and in revised form 20 February 1998     

Effect of age and gender on dopamine transporter imaging with [123I]FP-CIT SPET in healthy volunteers

Dopamine transporter imaging is a valuable tool to investigate the integrity of the dopaminergic neurons. To date, several reports have shown an age-associated decline in dopamine transporters in healthy volunteers. Although animal studies suggest an effect of gender on dopamine transporter density, this gender effect has not yet been confirmed in human studies. To study the influence of age and gender on dopamine transporter imaging in healthy volunteers, we performed single-photon emission tomography imaging with [¹²³I]FP-CIT to quantify dopamine transporters. Forty-five healthy volunteers (23 males and 22 females) were included, ranging in age from 18 to 83 years. SPET imaging was performed 3 h after injection of ±110 MBq [¹²³I]FP-CIT. An operator-independent volume of interest analysis was used for quantification of [¹²³I]FP-CIT binding in the striatum. The ratio of specific striatal to non-specific [¹²³I]FP-CIT binding was found to decrease significantly with age. Moreover, we found a high variance in [¹²³I]FP-CIT binding in young adults. Finally, females were found to have significantly higher [¹²³I]FP-CIT binding ratios than males. This effect of gender on [¹²³I]FP-CIT binding ratios was not related to age. The results of this study are consistent with findings from previous studies, which showed that dopamine transporter density declines with age. The intriguing finding of a higher dopamine transporter density in females than in males is in line with findings from animal studies. Received 29 January 2000 and in revised form 27 March 2000     

[123I]FP-CIT binding in rat brain after acute and sub-chronic administration of dopaminergic medication

The recently developed radioligand [¹²³I]FP-CIT is suitable for clinical single-photon emission tomography (SPET) imaging of the dopamine (DA) transporter in vivo. To date it has remained unclear whether dopaminergic medication influences the striatal [¹²³I]FP-CIT binding. The purpose of this study was to investigate the influence of this medication on [¹²³I]FP-CIT binding in the brain. We used an animal model in which we administered dopaminomimetics, antipsychotics and an antidepressant. In vivo [¹²³I]FP-CIT binding to the DA and serotonin transporters was evaluated after sub-chronic and acute administration of the drugs. The administered medication induced small changes in striatal [¹²³I]FP-CIT binding which were not statistically significant. As expected, the DA reuptake blocker GBR 12,909 induced a significant decrease in [¹²³I]FP-CIT binding. [¹²³I]FP-CIT binding in the serotonin-rich hypothalamus was decreased only after acute administration of fluvoxamine. The results of this study suggest that dopaminergic medication will not affect the results of DA transporter SPET imaging with [¹²³I]FP-CIT. Received 15 August and in revised form 15 October 1999     

New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. part 2: in vivo pharmacological characterization

On the basis of the observed high selective binding to both the human and rat progesterone receptor (PR) in vitro, three 17-iodovinyl-substituted nortestosterone derivatives, i.e., the Z-isomer of 17-iodovinyl-19-nortestosterone (Z-IVNT; Z-IPG1) and both the stereoisomers of 17-iodovinyl-18-methyl-11-methylene-19-nortestosterone (E-and Z-IPG2), were selected for radio-iodination and subsequently evaluated as potential radioligands for PR imaging in human breast cancer. Their target tissue uptake, retention, and uptake selectivity were studied in female rats. The distribution studies revealed that PR-mediated uptake in the uterus and ovaries could only be demonstrated for Z-[¹²³I]IPG2. The target tissue uptake selectivity was, however, low, with the highest uterus-to-nontarget tissue uptake ratios observed at 2–4 h postinjection (p.i.), being 4.4, 1.8, and 7.4 for the uterus-to-blood, -fat, and -muscle ratio, respectively. For Z-[¹²³I]IPG2, distribution was also studied in dimethylbenzanthracene (DMBA)-induced mammary tumour-bearing rats and in normal rabbits. Mammary tumour uptake of Z-[¹²³I]IPG2 in the mammary tumour-bearing rat was also found to be PR-specific. In rabbits, higher selective target tissue uptake of Z-[¹²³I]IPG2 was observed than in rats, resulting in uterus-to-blood, -fat, and -muscle ratios of 6.6, 2.2, and 21.3 at 2–4 h p.i., respectively. In conclusion, Z-[¹²³I]IPG2, which displayed high binding affinity for both the human and rat PR in vitro, showed specific PR-mediated target tissue uptake in rats and rabbits in vivo, the uptake selectivity being highest in the latter. Because the binding characteristics appeared to vary between species, a pilot study in breast cancer patients may be needed to decide whether Z-[¹²³I]IPG2 can be of potential use as PR imaging agent in breast cancer.     

Combined SPECT/CT imaging using 123I-IMT in the detection of recurrent or persistent head and neck cancer

The aim of the study was to assess the clinical value of combined SPECT/CT imaging using L-3-[123I]iodine--methyl tyrosine (IMT) for the differential diagnosis of recurrences in patients pre-treated for head and neck cancer. Thirty-four consecutive patients with biopsy-proven carcinomas, who had previously been treated by surgery and/or radio/chemotherapy, were examined at our clinic by IMT-SPECT using a dual-head system with integrated low-dose CT. SPECT results were correlated with histopathology, clinical and CT/MRI follow-up data. In the follow-up after SPECT examination, the final diagnosis of recurrent tumour was established in 26 patients; the remaining eight patients were recurrence-free (follow-up >6 months). IMT-SPECT/CT correctly detected recurrent disease and/or neck lymph node metastases in 22 patients. In addition, distant metastases were displayed in two patients. The study was false-negative in four patients (sensitivity 85%). True-negative results were registered in seven patients, and false-positive in one patient. Image fusion with coregistered low-dose CT facilitates the localisation and interpretation of IMT-SPECT findings. IMT-SPECT using integrated low-dose CT is a promising non-invasive imaging tool for the detection of head and neck cancer recurrences and their differentiation from treatment-induced changes.     

Methodological aspects for in vitro characterization of receptor binding using C-labeled receptor ligands: A detailed study with the benzodiazepine receptor antagonist [C]Ro 15-1788

As a complement to in vivo studies with positron emission tomography (PET), it is desirable to perform in vitro characterization of newly developed ¹¹C tracers. In this report we describe the technique for determination of receptor-ligand kinetics utilizing ligands labeled with the short-lived radionuclide ¹¹C. The limitations and advantages are discussed. The benzodiazepine antagonist [¹¹C]Ro 15-1788 was used as a model substance, and the use of storage phosphor plates for quantification of radioactivity was validated. Storage phosphor plates showed an excellent linear range (˜10³) and acceptable resolution (˜ 0.5 mm). Receptor-ligand kinetics, including depletion, association and dissociation, saturation and displacement were evaluated with good results through the use of short-lived radiotracers and storage phosphor plates.     

New iodinated progestins as potential ligands for progesterone receptor imaging in breast cancer. part 1: synthesis and in vitro pharmacological characterization

Five putative iodinated progesterone receptor (PR) binding ligands were synthesized and evaluated as potential imaging agents for PR-positive human breast tumours. Two compounds (E- and Z-17-hydroxy-21-iodo-19-nor-17-pregna-4,20-dien-3-one; E- and Z-IPG1) were previously described, but are re-evaluated. The other three were novel compounds: two nortestosterone analogues derived from ORG 3236 (E- and Z-13-ethyl-17-hydroxy-21-iodo-11-methylene-18,19-dinor-17-pregna-4,20-diene-3-one; E- and Z-IPG2) and one norprogesterone analogue derived from ORG 2058 (21-[4-iodophenoxy]-16-ethyl-19-norpregn-4-ene-3,20-dione; IPG3). The E-iodovinyl nortestosterone compounds were obtained by a new route of synthesis. Competitive binding studies were performed to determine their binding affinities for the PR in three types of tissue (human MCF-7 breast tumour cells and rat uterine and mammary tumour tissue) and for the androgen receptor (AR) in human MCF-7 breast tumour cells, as well as for the sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) in human plasma. All four 17-iodovinyl nortestosterone derivatives displayed high binding affinity for the human PR, that of Z-IPG1 and E- and Z-IPG2 being even higher than that of ORG2058. Their affinities for the rat PR were somewhat lower, especially those of both E-isomers. The affinity of IPG3 was lower for both the human and rat PR. The nortestosterone derivatives also showed AR binding, the relative binding affinities ranging from 4.3 to 17.0% as compared with 5DHT. Additionally, neither of these steroids displayed any significant binding to either SHBG or CBG in human plasma. We conclude that the in vitro binding properties of all four 17-iodovinyl nortestosterone derivatives warrant evaluation of the distribution characteristics of their ¹²³I-labelled analogues to determine their usefulness as PR imaging agents.     

Synthesis and in vivo evaluation of [C]methyl-Ro 64-6198 as an ORL1 receptor imaging agent

(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-3-N-[¹¹C]methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one ([¹¹C]methyl-Ro 64-6198), a N-methylated analog of Ro 64-6198, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain nociceptin/orphanin FQ receptors (ORL1 receptors) by positron emission tomography. A racemate of methyl-Ro 64-6198, Ro 66-7931, showed a high affinity and selectivity for the ORL1 receptor in vitro. An in vivo distribution study in mice demonstrated moderate brain uptake, however, only slight difference was observed among brain regions. Furthermore, pretreating with nociceptin or Ro 66-7931 did not affect the accumulation. Therefore, despite its high affinity, [¹¹C]methyl-Ro 64-6198 does not appear to be a suitable tracer for in vivo ORL1 receptor imaging studies.     

Synthesis and in vivo evaluation of [11C]methyl-Ro 64-6198 as an ORL1 receptor imaging agent.

(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-3-N-[¹¹C]methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one ([¹¹C]methyl-Ro 64-6198), a N-methylated analog of Ro 64-6198, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain nociceptin/orphanin FQ receptors (ORL1 receptors) by positron emission tomography. A racemate of methyl-Ro 64-6198, Ro 66-7931, showed a high affinity and selectivity for the ORL1 receptor in vitro. An in vivo distribution study in mice demonstrated moderate brain uptake, however, only slight difference was observed among brain regions. Furthermore, pretreating with nociceptin or Ro 66-7931 did not affect the accumulation. Therefore, despite its high affinity, [¹¹C]methyl-Ro 64-6198 does not appear to be a suitable tracer for in vivo ORL1 receptor imaging studies.     

5-[<Superscript>123</Superscript>I]Iodo-A-85380: assessment of pharmacological safety,radiation dosimetry and SPECT imaging of brain nicotinic receptors in healthy human subjects

Recently, 5-[123I]iodo-3-(2(S)-azetidinylmethoxy)pyridine ([123I]5IA) was developed as a ligand for imaging the nicotinic acetylcholine receptor (nAChR) in human brain using single photon emission computed tomography (SPECT). In the present study, the toxicity and radiation absorbed dose of [123I]5IA were investigated. Behavior and physiological parameters were examined in mice and rats after administration of 5IA. There were no changes in these parameters in animals administered 1 microg/kg of 5IA or less, indicating that the no observed effect level (NOEL) of 5IA was 1 microg/kg. [123I]5IA was then administered to healthy human subjects and serial whole-body images were acquired over 24 hr. Initially, high levels of radioactivity were observed in the liver and urinary bladder and moderate levels in the lungs, kidneys, and brain. Whole brain activity at 1 hr was 4.6 +/- 0.4% of the injected dose and this value gradually decreased with time. The majority (-75%) of the radioactivity was excreted in urine within 24 hr, and less than 1% remained in all organs tested. The biological half-life of [1231]51A averaged 7.2 +/- 4.0 hr. Based on the biodistribution data, radiation absorbed doses were estimated using MIRDOSE 3.1 software with the dynamic bladder model and the ICRP gastrointestinal (GI) tract model. Consequently, the effective dose equivalent was estimated to be 30 +/- 1.4 microSv/MBq, which is an acceptable radiation burden. Having determined the safety of this compound, we performed SPECT imaging in a healthy human subject using 171 MBq of [123I]5IA. SPECT images clearly revealed a cerebral distribution of radioactivity that was consistent with the known distribution of central nAChRs in humans. These results suggest that [123I]5IA is a promising ligand for imaging nAChRs in humans, with an acceptable dosimetry and pharmacological safety at the dose required for adequate SPECT imaging.     

N-(n-benzylpiperidin-4-yl)-2-[f]fluorobenzamide: a potential ligand for pet imaging of breast cancer

ABSTRACT. N-(N-Benzylpiperidin-4-yl)-2-[¹⁸F]fluorobenzamide (2), a potential ligand for PET imaging of sigma receptor, has been found to be a potential agent for detection of breast cancer. In vivo studies in severe combined immunodeficient (SCID) mice bearing MDA-MB231 tumors showed that the uptake of compound 2 in these tumors was high (3.8%/g); the ratios of tumor/muscle and tumor/blood were 6.2 and 7.0, respectively, at 1 h postinjection. Pretreatment of SCID mice with haldol increased the uptake of compound 2 in blood, muscle, and other well-perfused organs while decreasing its uptake in tumors. The ratios of tumor/muscle and tumor/blood decreased from 6.2 and 7.0 to 1.3 and 1.1, respectively, at 1 h postinjection. At 2 h postinjection, the ratios of tumor/muscle and tumor/blood decreased from 4.9 and 7.8 to 1.4 and 1.4, respectively. The tumor uptake of compound 2 in SCID mice bearing primary tumor explants from a human breast cancer patient was lower than that in MDA-MB231 tumors (1.66%/g versus 3.78%/g), and the ratios of tumor/muscle and tumor/blood were 3.5 and 3.7, respectively, at 1 h postinjection. These results suggest that compound 2 may be a potential ligand for PET imaging of breast cancer.     

[<Superscript>18</Superscript>F]Fluorinated estradiol derivatives for oestrogen receptor imaging: impact of substituents,formulation and specific activity on the biodistribution in breast tumour-bearing mice

PURPOSE: The biodistribution and tumour uptake of a series of 16alpha-[(18)F]fluoroestradiol ([18F]FES) derivatives was determined in oestrogen receptors-positive (ER+) tumour-bearing mice to assess the impact of substituents, formulation and specific activity on target tissue uptake. METHODS: MC4-L2 and MC7-L1 murine ER+ cells were inoculated in Balb/c mice. The animals were injected with various [(18)F]FES derivatives substituted with 2- or 4-fluorine and/or an 11beta-methoxy group. The radiopharmaceuticals were formulated in 10% ethanol/saline or 10% ethanol/lipid emulsion. The organs were counted, and radioactivity concentrations were expressed as the percentage of the injected dose per gram tissue (%ID/g). To estimate the effect of specific activity on tumour uptake, the 4-fluoro-11beta-methoxy-16alpha-[(18)F]-fluoroestradiol (4F-M[(18)F]FES) was co-injected with different concentrations of non-radioactive estradiol to give an in vivo competitive inhibition curve. RESULTS: 4F-M[(18)F]FES exhibited the highest average uterine uptake (%ID/g = 15.7 +/- 2.1). The highest uptake by the two mammary tumours was observed with [(18)F]FES (%ID/g = 3.1 and 3.4 +/- 0.3) and 11beta-methoxy-16alpha[(18)F]-fluoroestradiol (M-[(18)F]FES) (%ID/g = 3.2 and 3.3 +/- 0.6), followed by 4F-M[(18)F]FES (%ID/g = 2.5 and 2.3 +/- 0.3). The formulation had little influence on the biodistribution pattern. Co-injection with a total mass of estradiol >10(-10) mol blocked 4F-M[(18)F]FES tumour uptake. CONCLUSION: All of the radiolabelled estradiol derivatives achieved significant target tissue uptake in vivo, both in ER+ tumours and the uterus. The formulation had little impact on the biodistribution of these compounds but some compounds (4F-M[(18)F]FES, M-[(18)F]FES and [(18)F]FES) had more favourable target tissue uptake and target-to-background ratios.     

O-(2-[18F]Fluoroethyl)-l-tyrosine and l-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study

O-(2-[¹⁸F]Fluoroethyl)-l-tyrosine (FET) is a recently described amino acid analogue that has shown high accumulation in animal tumours. The aim of this study was to compare the uptake of FET with that of l-[methyl-¹¹C]methionine (MET) in patients with suspected primary or recurrent intracerebral tumours. Sixteen consecutive patients with intracerebral lesions were studied on the same day by positron emission tomography (PET) using MET and FET. Uptake of FET and MET was quantified by standardized uptake values. Tracer kinetics for normal brain and intracerebral lesions were compared. On the basis of the MET-PET studies, viable tumour tissue was found in 13 patients. All tumours showed rapid uptake of FET and were visualized with high contrast. Mean uptake of FET for normal grey matter, white matter and tumour tissue was 1.1±0.2, 0.8±0.2 and 2.7±0.8 SUV, respectively. In all three tissues, uptake of MET was slightly higher (1.4±0.2, 0.9±0.1 and 3.3±1.0 SUV; P<0.01). However, contrast between tumour and normal tissues was not significantly different between MET and FET. Uptake of FET in non-neoplastic lesions (1.0±0.1 SUV) was significantly lower than in tumour tissue (P=0.007). For all lesions there was a close correlation (r=0.98) between MET and FET uptake. In conclusion, in PET studies of human brain tumours, the uptake and image contrast of FET appear to be very similar to those of MET. The specificity of FET for tumour tissue is promising but has to be addressed in a larger series of patients with non-neoplastic lesions. Received 24 October 1999 and in revised form 19 January 2000     

The stereoisomers of 17α-[123I]iodovinyloestradiol and its 11α-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus,and their distribution in immature rats

We studied the potential of both stereoisomers of 17-[¹²³I]iodovinyloestradiol (E- andZ-[¹²³I]IVE) and of 11-methoxy-17-[¹²³I]iodovinyloestradiol (E-andZ-[¹²³I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17-[¹²³I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17-tri-n-butylstannylvi-nyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17-iodovinyloes-tradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their¹²³I-labelled analogues were studied in immature female rats. All four 17-iodovi-nyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE E-IVE. Neither of these 17-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that ofE- andZ-[¹²³I]MIVE being higher than that ofE- andZ-[¹²³I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24 h), were exhibited by both isomers of [¹²³I]MIVE. The uterus-to-blood uptake ratio was higher for^E-[¹²³I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for theZ-isomer of [¹²³I]MIVE, especially at 24 h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude thatE- andZ-[¹²³I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted.     

Detection of metastatic lesions from malignant pheochromocytoma and paraganglioma with diffusion-weighted magnetic resonance imaging: comparison with 18F-FDG positron emission tomography and 123I-MIBG scintigraphy

OBJECTIVE: To investigate the diagnostic features of whole-body diffusion-weighted magnetic resonance imaging (DWI) as compared with 2-[(18)F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and (123)I-meta-iodo-benzyl guanidine scintigraphy (MIBG) on metastatic lesions of patients with malignant pheochromocytoma or paraganglioma. METHODS: We prospectively studied 11 patients with histologically confirmed pheochromocytoma/paraganglioma and possible metastatic lesions. FDG-PET, MIBG, and DWI examinations were performed within 1 week, and the images were visually interpreted. Abnormal positive uptake either on MIBG or on FDG-PET was considered as metastases. Abnormal high signal intensities on DWI were considered as metastases using conventional T1-and T2-weighted images as reference. RESULTS: FDG-PET and DWI demonstrated metastatic lesions in all 11 patients, but MIBG showed no metastatic lesions in two patients. The numbers of lymph node metastases depicted on FDG-PET, MIBG, and DWI were 19, 6, and 39; bone metastases were 50, 49, and 60; liver metastases were 9, 9, and 15; lung metastases were 5, 7, and 5, respectively. MIBG failed to demonstrate many metastatic lesions, which were demonstrated on FDG-PET or DWI, although two mediastinal lymph node metastases, three lung metastases, and six bone metastases, which were not seen on DWI, were clearly demonstrated on MIBG. DWI showed 15 liver metastases, but 6 of them were not seen on FDG-PET or MIBG. CONCLUSIONS: DWI may be particularly advantageous in depicting lymph node and liver metastases and may have a higher rate of detecting metastatic lesions when compared with MIBG or FDG-PET. The limitations of DWI were possible false-positive finding, and probable lower detectability of mediastinal lymph node and lung metastasis.