Estimation of local cerebral glucose utilization by positron emission tomography: comparison of [18F]2-fluoro-2-deoxy-D-glucose and [18F]2-fluoro-2-deoxy-D-mannose in patients with focal brain lesions.

A comparative PET study of [18F]2-fluoro-2-deoxy-D-glucose (FDG) and [18F]2-fluoro-2-deoxy-D-mannose (FDM) uptake was performed in 13 patients with focal brain lesions. Differences between FDG and FDM with respect to model rate constants, lumped constant, and estimated metabolic rate for glucose were determined on a regional basis. Across whole brain, the transport rate constant K1* was almost unchanged, whereas k2*, describing the transport back from tissue to plasma, was 6% higher, and the phosphorylation rate constant k3* was 9% lower for FDM compared to FDG. This implies a 20% lower lumped constant for FDM. No significant regional variability of this differential tracer behavior was observed in normal or in lesioned brain tissue. Thus, results from previous FDG studies, where the radiotracer was not 100% pure FDG but contained varying amounts of FDM, can easily be corrected by adjustment of the lumped constant employed in metabolic quantitation.

Synthesis of high specific activity [75Br]- and [77Br]bromperidol and tissue distribution studies in the rat.

A rapid synthesis of [75Br]- and [77Br]bromperidol with specific activity exceeding 10000 Ci/mmol is described in which a trimethylstannylated analogue of bromperidol is used as a substrate for regiospecific no-carrier-added radiobromination. 4-[4-[4-(Trimethylstannyl)phenyl]-4-hydroxypiperidino]-4'- fluorobutyrophenone was synthesized by the reaction of (trimethylstannyl)sodium with haloperidol and purified by preparative HPLC. Subsequent radiobromination with no-carrier-added 75Br- or 77Br- and in situ oxidation using H2O2/CH3COOH gave a corrected radiochemical yield of 35% with a 30-min preparation time. Tissue distribution studies in the rat show a rapid and prolonged uptake into the brain, liver, and kidneys and consistently low blood concentrations that differ quantitatively from previous studies using relatively low specific activity bromperidol. Potential clinical applications for this high specific activity radiobrominated neuroleptic are discussed.

Bromine-75-labeled 1,4-benzodiazepines: potential agents for the mapping of benzodiazepine receptors in vivo: concise communication.

We have prepared four different 1,4-benzodiazepines, labeled at C-7 with the 1.6-hr positron emitter Br-75 or the 57-hr gamma emitter Br-77, as potential radio-pharmaceuticals for the mapping of cerebral benzodiazepine receptor areas. The triazene method was used and optimized. Yields at the no-carrier-added level were 20%. 7-[75Br]-5-(2-fluorophenyl)-1-methyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Br-75 BFB) was isolated with a minimum specific activity of 20,000 Ci/mmole. Biodistribution in mice shows that BFB is taken up rapidly by the brain and is retained there at useful concentrations for significant periods of time. The maximum uptake is observed at 0.25 min. Brain-to-blood concentration ratios are larger than 2 during the interval (0.25 to 10 min) investigated.

Cerebral metabolism of L-[2-18F]fluorotyrosine, a new PET tracer of protein synthesis.

L-[2-18F]fluorotyrosine (2-18FTyr) was evaluated as a tracer of cerebral protein synthesis for positron emission tomography (PET). Its metabolism in murine cerebrum was studied. The uptake in brain reaches a value of approximately 2% of the injected dose per gram tissue after 60 min. The incorporation of the tracer into tissue proteins was proven by discontinuous SDS gel electrophoresis. The protein bound fraction of tissue activity increased to 84% and 89% after 60 and 120 min p.i., respectively. High performance liquid chromatography analysis showed a concomitant decrease of free 2-18FTyr in tissue with time. The sum of free 2-18FTyr, tRNA-and protein-bound 2-18FTyr in cerebral tissue gave an almost quantitative activity balance of 96 +/- 4% at all times examined. A significant formation of fluorodopa or fluorodopamine must therefore be excluded. This shows that L-[2-18F]fluorotyrosine is a promising tracer for quantitation of protein synthesis rates with PET based on a three-compartment model.

14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA): evaluation in mouse of a new probe of myocardial utilization of long chain fatty acids.

14(R,S)-[18F]Fluoro-6-thia-heptadecanoic acid (FTHA) is a new radiolabeled long-chain fatty acid (LCFA) analog designed to undergo metabolic trapping subsequent to its commitment to the beta-oxidation pathway. Sulfur-substitution at the sixth carbon of FTHA causes a prolonging of myocardial clearance half-time (T 1/2 approximately 2 hr) in mice with little diminution of myocardial uptake (39.8 +/- 3.0% ID/g at 5 min). Heart-to-blood ratios were 20 +/- 6 and 82 +/- 16 at 1 and 60 min, respectively. In contrast, the 3-thia analog, 13(R,S)-[18F]-fluoro-3-thia-hexadecanoic acid, showed lower uptake and poor retention by heart. Myocardial uptake of FTHA was reduced by 81% (p less than 10(-5) and 87% (p less than 5 x 10(-4] in mice pretreated with the carnitine palmitoyltransferase I inhibitor, 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA) at 1 and 60 min, respectively. Radioanalytical studies showed the major metabolic fate of FTHA in control and POCA treated myocardium to be unidentified metabolite(s) that bind to tissue protein. Smaller amounts of 18F radioactivity were present in myocardium as complex lipids, fatty acid, and unidentified soluble metabolites. The results indicate metabolic trapping of FTHA in myocardium subsequent to its entry into the mitochondrion and encourage its further evaluation as a PET tracer of myocardial LCFA utilization.

Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution.

An aminopolyether mediated synthesis of fluorine-18 (18F) 2-fluoro-2-deoxy-D-glucose (FDG) has been developed. The nucleophilic fluorination with accelerator-produced [18F]fluoride works at the no-carrier-added level and gives epimerically pure 2-18FDG with an uncorrected radiochemical yield of a maximum 50% in a synthesis time of approximately 50 min from EOB.

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.

Accumulation of radioiodinated L-alpha-methyltyrosine in pancreas of mice: concise communication.

L-3-iodo-alpha-methyltyrosine, labeled with either I-131 or I-123, has a high pancreatic specificity in mice. A pancreas-to-liver ratio of 8.6 +/- 2.7 is observed during the first hour after i.v. injection. Accumulation is also prominent in the kidneys, but excretion of the radioagent is rapid, 50% of the activity being eliminated during 90 min. Compared with L-[75Se]selenomethionine, the compound currently used for pancreatic imaging, L-3-[123I]or[131I]iodo-alpha-methyltyrosine has a higher pancreas-to-liver ratio, a shorter physical half-life and biological half-time, and better decay characteristics.

15-(p[75Br]bromophenyl)pentadecanoic acid: pharmacokinetics and potential as heart agent.

Preparation, quality control, and pharmacokinetics of 15-(p-[75Br]bromophenyl)pentadecanoic acid (BPPA) were studied, with particular emphasis on the fate of the label and the usefulness of BPPA as a heart agent. BPPA labeled with the positron emitter Br-75 (T 1/2 = 98 min) was prepared in 55% radiochemical yield with a specific activity of greater than or equal to 1000 Ci/mmol. While the uptake of BPPA in the heart muscle is as fast and efficient as that of aliphatic omega-halofatty acids, its elimination is delayed, owing mainly to an inhibited beta oxidation and the formation of lipophilic catabolites. The blood activity and its time course are identical to those of omega-halofatty acids, but no free bromide appears in any body fluid or organ. The complex pharmacokinetic behavior of stable lipophilic catabolites prevents a quantitative background correction. In contrast to aliphatic omega-halofatty acids, a quantitative evaluation of myocardial metabolism is not possible. Br-75 BPPA, however, is well suited for positron emission tomography of the heart.

Metabolic mismatch of septal beta-oxidation and glucose utilization in left bundle branch block assessed with PET.

Preserved septal uptake of the new long-chain fatty acid analog [18F]FTHA was found in a patient with three-vessel disease, a history of previous anterior myocardial infarction and left bundle branch block (LBBB), despite severely decreased septal [18F]FDG uptake that suggested scarred tissue. Nearly absent [19F]FDG uptake in the septum could not be explained by concordant reduction of septal perfusion as assessed by 99mTc-MIBI SPECT. These data may point to divergent metabolic effects of the conduction abnormality in LBBB with consecutively reduced septal exogenous glucose utilization but unaffected septal beta-oxidation.

Comparative evaluation of fatty acids labeled with C-11, Cl-34m, Br-77, and I-123 for metabolic studies of the myocardium: concise communication.

Various long-chain fatty acids have been labeled with C-11, Cl-34m, Br-77, and I-123 and evaluated for their potential application in measuring myocardial metabolism in vivo. Comparative studies of the kinetics of accumulation and clearance from the heart muscle of mice indicate that the extraction of omega-halofatty acids is more efficient than that of alpha-halofatty acids. Among the omega-halofatty acids, the highest uptake is observed for the 17-iodoheptadecanoic acid, which shows an extraction behavior almost identical to that of [1-11C] palmitic acid, although with a higher radioactivity level in blood due to the release of free iodide.

Increased amino acid transport into brain tumors measured by PET of L-(2-18F)fluorotyrosine.

The uptake of L-(2-18F)fluorotyrosine (F-Tyr), a newly synthetized amino acid tracer, was studied in 15 patients with various brain tumors by dynamic PET. The higher F-Tyr accumulation in tumors (mean 27% above contralateral tissue) was associated with two-fold transport rates into tumors, while the rate constants describing irreversible incorporation were decreased. The increased F-Tyr transport was not correlated to 68Ga-EDTA accumulation and cannot be explained by disruption of the blood-brain barrier. Kinetic analysis of 2-(18F)-fluoro-deoxy-glucose accumulation in the same patients demonstrated that increased metabolic rates in tumors are mainly caused by altered phosphorylation rates while transport of glucose is less affected. Since F-Tyr transport rates clearly separated tumors from normal tissue and since F-Tyr accumulation was related to tumor grade, PET studies of F-Tyr uptake are of clinical value for diagnosis and classification of brain tumors.

Measurement of pharmacokinetics of yttrium-86 radiopharmaceuticals with PET and radiation dose calculation of analogous yttrium-90 radiotherapeutics.

This study was performed to demonstrate the quantitative in vivo assessment of human pharmacokinetics of 90Y-radiotherapeutics using the positron-emitting substitute 86Y and PET. This technique is illustrated in a patient with disseminated bone metastases from breast cancer who was injected with 100 MBq of 86Y-citrate as an analog of the commercially available radiotherapeutic 90Y-citrate. Whole-body distribution was measured with a PET camera 4, 10, 21, 28 and 45 hr postinjection. Uptake data were determined from reconstructed transverse PET images by regions of interest placed in normal bone tissue, liver and metastases. Images of coronal and sagittal whole-body sections were obtained by reformatting the transverse PET images. The ratio of activity concentration in metastases to that in normal bone ranged from 1.5:1 to 3.5:1. Of the injected tracer, 13.4% was found in the skeleton and 0.43% in the metastasis with the highest 86Y concentration. Radiation doses per 1 MBq of injected 90Y-citrate were calculated from 86Y-citrate data and data from MIRD pamphlets 5 and 11. The doses were 1.01 MGy/MBq for red marrow, 593 microGy/MBq for the liver and approximately 3.5 MGy/MBq for the most conspicuous metastases. This study demonstrates that the use of PET via 86Y allows an individual in vivo quantification of activity uptake and radiation dose of both normal tissue and tumor in pain treatment with 90Y-labeled radiotherapeutics.

Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging.

UNLABELLED: The aim of the study was to develop a simple 18F-labeled amino acid as a PET tracer for cerebral and peripheral tumors. O-(2-[18F]fluoroethyl)-L-tyrosine (L-[18F]FET) was synthesized and biologically evaluated. Results of the first human PET study are reported. METHODS: No carrier added (n.c.a.) and D-[18F]FET were prepared by 18F-fluoroethylation of L- and D-tyrosine in a two-step procedure. Biodistribution studies were performed in mice. The metabolic fate of L-[18F]FET was investigated in plasma, brain, tumor and pancreatic tissue samples using chromatographic procedures. Tumor uptake studies were performed in mammary carcinoma-bearing mice and in mice with the colon carcinoma SW 707. In a human PET study, a 59-y-old man with a recurrent astrocytoma was imaged using n.c.a. L-[18F]FET. RESULTS: Synthesis of [18F]FET was accomplished in about 50 min with an overall radiochemical yield of 40%. The uptake of L-[18F]FET in the brain of mice reached a level >2% ID/g between 30 and 60 min postinjection. The brain uptake of the D-isomer was negligible, indicating blood-brain barrier penetration by a specific amino acid transport system. L-[18F]FET is not incorporated into proteins. High-performance liquid chromatography (HPLC) analysis of brain, pancreas and tumor homogenates as well as plasma samples of mice at 10, 40 or 60 min postinjection showed only unchanged L-[18F]FET. Activity uptake in the bone did not exceed 2% ID/g at 40 min postinjection. The brain uptake of L-[18F]FET in mice bearing mammary carcinomas and colon carcinomas reached 7.1%+/-1.2% ID/g and 6.4%+/-1.7% ID/g 1h postinjection, respectively. In the first human study, L-[18F]FET-PET allowed a clear delineation of a recurrent astrocytoma. Thirty-five minutes postinjection, the tumor-to-cortex ratio was >2.7. A tumor-to-blood ratio >1.5 was reached at 30 min postinjection and continued to increase. No significant activity accumulation was observed in peripheral organs after approximately 40 min postinjection. CONCLUSION: The high in vivo stability of L-[18F]FET, its fast brain and tumor uptake kinetics, its low accumulation in nontumor tissue and its ease of synthesis strongly support further evaluation of L-[18F]FET as an amino acid tracer for cerebral and peripheral tumors.

Myocardial imaging and metabolic studies with [17-123I]iodoheptadecanoic acid.

After intravenous administration of the stearic acid analogue [17-123I]iodoheptadecanoic acid (I-123 HA), myocardial metabolism was studied in ten normal individuals, eight patients with coronary artery disease and three patients with congestive heart failure. High-quality images were obtained in sequential scintigraphy of I-123 metabolically bound in myocardial tissue. Infarcted zones as well as ischemic regions are indicated by reduced tracer uptake. Iodine-123 in the blood pool and interstitial space consists mainly of radioiodide that is liberated by fatty-acid metabolism and was corrected for. Using the proposed correction not only are the images improved but the uptake and elimination of the I-123 in the myocardial cells can be followed. The average disappearance half-time of I-123 HA from the myocardium of normal persons was 24 +/- 4.7 min. In patients with coronary artery disease significant differences between myocardial regions were observed.

Brain and brain tumor uptake of L-3-[123I]iodo-alpha-methyl tyrosine: competition with natural L-amino acids.

SPECT studies with L-3-[123I]iodo-alpha-methyl tyrosine (IMT) were carried out in 10 patients with different types of brain tumors--first under fasting conditions (basal) and a week later during intravenous infusion of a mixture of naturally-occurring L-amino acids (AA load). An uptake index (UI) was calculated by dividing tissue count rates by the integral of plasma count rates. The UI decreased by 45.6% +/- 15.4% (n = 10, p less than 0.001) for normal brain and by 53.2% +/- 14.1% for gliomas (n = 5, p less than 0.01) during AA load compared to basal conditions, while two meningiomas and a metastasis showed only a minor decrease (23.9 +/- 5.7%, n.s.). Two pituitary adenomas could not be delineated on the SPECT scans. These data indicate that IMT competes with naturally-occurring L-amino acids for transport into normal brain and gliomas. Transport characteristics of IMT into tumors of nonglial origin appear to be different from those of gliomas. For both types of tumors, it is advisable to perform IMT-SPECT under fasting conditions.

Noninvasive assessment of regional cardiac adenosine using positron emission tomography.

One of the early metabolic changes associated with myocardial ischemia is the breakdown of adenine nucleotides resulting in the enhanced production of adenosine. In order to image regional cardiac adenosine by positron emission tomography (PET) the enzymatic conversion of adenosine into [11C]-S-adenosylhomocysteine ([11C]SAH) was used in the presence of 11C-labeled homocysteine thiolactone (adenosine + [11C] - homocysteine-->[11C] - SAH + H2O). Following production of an experimental coronary constriction in anesthetized dogs carrier added 1-[11C]-D,L-homocysteine thiolactone (5-27 mCi, 30 mg/kg) was infused over 1 min. This intervention, while hemodynamically ineffective, increased the plasma homocysteine concentration from 2.5 to 306 microM, which thereafter declined with a T1/2 of 28 min to 97 microM after 60 min. During the first minutes following infusion of [11C] homocysteine, the radioactivity concentration in the blood pool, the nonischemic and the ischemic myocardium were similar. Between 20 and 60 min, however, the regional radioactivity concentration was highest in the perfusion area of the stenosed vessel: 6.6% compared to 5.2 and 5.2% of the injected dose per 1 I tissue. The elevated radioactivity concentration was strictly confined to the perfusion area of the occluded artery. Using [35S]-L-homocysteine (20 microCi; 30 mg/kg) chromatographic separation of SAH in tissue extracts confirmed that the radioactivity accumulation was due to trapping of adenosine in the cellular SAH-pool. These experiments provide first evidence that 1-[11C]homocysteine thiolactone can be successfully used to assess regional adenosine formation in the heart with PET via measurement of [11C] SAH accumulation.

Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting.

UNLABELLED: The alpha(v)beta3 integrins play an important role during tumor metastasis and tumor-induced angiogenesis. Targeting of this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Cyclo(-Arg-Gly-Asp-D-Phe-Val-) has been shown to be a selective alpha(v)beta3 integrin antagonist with high affinity. In this study we describe the synthesis and biological evaluation of [125I]-3-iodo-D-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) ([125I]P2), [125I]-3-iodo-Tyr5-cyclo(-Arg-Gly-Asp-D-Phe-Tyr-) ([125I]P4) and the negative control peptide [1251]-3-iodo-D-Tyr4-cyclo(-Arg-D-Ala-Asp-Tyr-Val-) ([125I]P6). METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl amino acid coupling protocols. Radioiodination was performed using the iodogen method. The in vitro binding assays were performed using isolated, immobilized alphaIIbeta3 and alpha(v)beta3 integrins. Expression of the alphaVbeta3 receptor on the different tumors was validated by immunohistochemical methods using alpha(v) and alpha(v)beta3 specific antibodies. For biodistribution studies, nude mice with melanoma M21 or mammary carcinoma MaCaF and BALB/c mice with osteosarcoma were used. RESULTS: The in vitro binding assays demonstrate that the introduction of tyrosine and subsequent iodination have no influence on the high affinity and selectivity for alpha(v)beta3. Immunohistochemical staining clearly indicates the presence of the alpha(v)beta3 integrins on the tumor tissue of the melanoma and the osteosarcoma. Pretreatment and displacement studies show specific binding of [125I]P2 on melanoma M21-bearing nude mice and osteosarcoma-bearing BALB/c mice but less specific binding on mammary carcinomas. [125I]P2 exhibits fast elimination kinetics. The accumulation in the tumor 10 min postinjection is 2.07 +/- 0.32 %ID/g for the melanoma M21 and 3.50 +/- 0.49 %ID/g for the osteosarcoma and decreases to 1.30 +/- 0.13 %ID/g and 2.03 +/- 0.49 %ID/g 60 min postinjection, respectively. [125I]P4 shows even faster elimination kinetics, resulting in a tumor accumulation of 0.40 +/- 0.10 %ID/g 60 min postinjection for the osteosarcoma-bearing BALB/c mice. Both peptides reveal predominately hepatobiliary excretion. For [1251]P2, this also is confirmed by autoradiography. The negative control peptide [125I]P6 shows no specific activity accumulation. CONCLUSION: [125I]P2 exhibits high affinity and selectivity for the alpha(v)beta3 integrin in vitro and in vivo and, thus, represents the first radiolabeled alpha(v)beta3 antagonist for the investigation of angiogenesis and metastasis in vivo.

Imaging of brain tumors with L-3-[123I]iodo-alpha-methyl tyrosine and SPECT.

Carbon-11-labeled amino acids have been successfully used to image brain tumors by PET. This study was undertaken to evaluate the potential of L-3-[123I]-iodo-alpha-methyl tyrosine (123IMT) for metabolic imaging of brain tumors. Ten patients (glioblastoma, oligodendroglioma, lymphoma, and metastases) had early and delayed brain SPECT with a rotating gamma camera after i.v.-injection of 200-300 MBq 123IMT. In nine patients the tumors showed intense uptake of the radiotracer. Tumor-to-brain tissue ratios were between 1.4 and 2.6. 123IMT shows potentials for monitoring the effects of brain tumor therapy.

SPECT studies of brain tumors with L-3-[123I] iodo-alpha-methyl tyrosine: comparison with PET, 124IMT and first clinical results.

L-3-[123I]iodo-alpha-methyltyrosine (123IMT) like tyrosine has been reported previously to have a high affinity for a transport system in the blood-brain-barrier (BBB). We examined the kinetic behavior of 124IMT in brain and plasma in two patients with glioblastoma using dynamic positron emission tomography (PET). 124IMT accumulated in brain and tumor tissue, reaching a maximum after 15 min, with a washout of 20% to 35% at 60 min postinjection. Animal experiments confirmed the accumulation of the intact tracer in murine brain, but there was no incorporation into proteins. SPECT studies with 123IMT in patients with different types of brain tumors showed increased uptake in 26 of 32 tumors. Although nonspecific uptake in tumors must be considered, the accumulation of IMT in normal brain and in some tumors with intact BBB suggests a specific uptake of IMT. As transport is the main determinant of initial amino acid uptake, 123IMT appears to be a suitable SPECT tracer of amino acid uptake although it is not incorporated into protein.