Sex affects myocardial blood flow and fatty acid substrate metabolism in humans with nonischemic heart failure.

BACKGROUND: In animal models of heart failure (HF), myocardial metabolism shifts from high-energy fatty acid (FA) metabolism toward glucose. However, FA (vs glucose) metabolism generates more ATP/mole; thus, FA metabolism may be especially advantageous in HF. Sex modulates myocardial blood flow (MBF) and substrate metabolism in normal humans. Whether sex affects MBF and metabolism in patients with HF is unknown. METHODS AND RESULTS: We studied 19 well-matched men and women with nonischemic HF (EF ≤ 35%). MBF and myocardial substrate metabolism were quantified using positron emission tomography. Women had higher MBF (mL/g/minute), FA uptake (mL/g/minute), and FA utilization (nmol/g/minute) (P < 0.005, P < 0.005, P < 0.05, respectively) and trended toward having higher FA oxidation than men (P = 0.09). These findings were independent of age, obesity, and insulin resistance. There were no sex-related differences in fasting myocardial glucose uptake or metabolism. Higher MBF was related to improved event-free survival (HR 0.31, P = 0.02). CONCLUSIONS: In nonischemic HF, women have higher MBF and FA uptake and metabolism than men, irrespective of age, obesity, or insulin resistance. Moreover, higher MBF portends a better prognosis. These sex-related differences should be taken into account in the development and targeting of novel agents aimed at modulating MBF and metabolism in HF.

Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the human heart.

Type 2 diabetes, obesity, and sex difference affect myocardial glucose uptake and utilization. However, their effect on the intramyocellular fate of glucose in humans has been unknown. How the heart uses glucose is important, because it affects energy production and oxygen efficiency, which in turn affect heart function and adaptability. We hypothesized that type 2 diabetes, sex difference, and obesity affect myocardial glucose oxidation, glycolysis, and glycogen production. In a first-in-human study, we measured intramyocardiocellular glucose metabolism from time-activity curves generated from previously obtained positron emission tomography scans of 110 subjects in 3 groups: nonobese, obese, and diabetes. Group and sex difference interacted in the prediction of all glucose uptake, utilization, and metabolism rates. Group independently predicted fractional glucose uptake and its components: glycolysis, glycogen deposition, and glucose oxidation rates. Sex difference predicted glycolysis rates. However, there were fewer differences in glucose metabolism between diabetic patients and others when plasma glucose levels were included in the modeling. The potentially detrimental effects of obesity and diabetes on myocardial glucose metabolism are more pronounced in men than women. This sex difference dimorphism needs to be taken into account in the design, trials, and application of metabolic modulator therapy. Slightly higher plasma glucose levels improve depressed glucose oxidation and glycogen deposition rates in diabetic patients.

Utilizing electrostatic interactions to facilitate F-18 radiolabeling of poly(amido)amine (PAMAM) dendrimers.

The development of methods for the facile conjugation and radiolabeling of poly(amido)amine (PAMAM) dendrimers would be of great benefit in evaluating biomedical applications of these intriguing molecularly defined polymers. Two anionic N-hydroxysuccinimide (NHS) esters (7 and 10) were developed and radiolabeled with fluorine-18 using Cu(I)-catalyzed click reactions. The radiolabeling of a primary amine-terminated PAMAM generation-6 (G6) dendrimer with [(18)F]7 or [(18)F]10 was complete in water or methanol within 5 min at room temperature. This highly efficient conjugation reaction benefits from a high, localized concentration of these NHS esters on the surface of PAMAM dendrimers, due to the electrostatic attraction between the anionic NHS esters and the positively-charged PAMAM dendrimers. The large medium effect (pH, salt, solvent) observed for these conjugation reactions is consistent with this mechanism. This novel strategy of utilizing electrostatic interactions provides a novel, facile, and efficient method for the conjugation and radiolabeling of PAMAM dendrimers that also has potential for radiolabeling other appropriate nanoparticles.

Optimization of the preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16beta-[18F]fluoro-5alpha-dihydrotestosterone (FDHT) as radiopharmaceuticals.

Fluorine-18-labeled steroid receptor tracers, 16α-[(18)F]fluoroestradiol (FES), [(18)F]fluoro furanyl norprogesterone (FFNP), and 16ß-[(18)F]fluoro-5α-dihydrotestosterone (FDHT), are important imaging tools for studies of breast and prostate cancers using positron emission tomography (PET). The automated production of these ligands with high specific activity (SA) as radiopharmaceuticals requires modification and optimization of the currently reported methods. [(18)F]FES with high SA was synthesized in over 60% radiochemical yield (RCY) at the end of synthesis (EOS) using a small amount of precursor (1) (as low as 0.3 mg) and 1 M H2SO4 for deprotection of the intermediate (2). [(18)F]FFNP was synthesized in up to 77% RCY at EOS using the triflate precursor (4) at room temperature or in 25% RCY using the mesylate precursor (6) at 65°C. Both methods are highly reproducible and afford high SA. [(18)F]FDHT was synthesized by radiofluoride incorporation at room temperature, reduction with NaBH4 , and deprotection with HCl/acetone, giving [(18)F]FDHT in up to 75% yield (RCY). All of these methods can be easily translated to automated production. The information provided here will aid in the development of automated production of these steroid receptor tracers with high or improved yields, optimal SA, and ease of processing for research and clinical use.

Early response assessment in prostate carcinoma by ¹8F-fluorothymidine following anticancer therapy with docetaxel using preclinical tumour models.

PURPOSE: The aim of the study was to assess the potential usefulness of 3-deoxy-3-(18)F-fluorothymidine (FLT) as a radiopharmaceutical for imaging the early therapeutic effects of docetaxel (DTX) on tumour proliferation in hormone-refractory prostate cancer (HRPC). METHODS: Cells of the androgen-independent human prostate tumour cell line, 22Rv1, were implanted in athymic male mice. Approximately 3 weeks after cell implantation, the mice were treated with DTX or vehicle. Before and after the treatment, the mice were imaged with a microPET-Focus-F120 scanner (Concorde Microsystems, Knoxville, TN, USA) using FLT and (18)F-fluorodeoxyglucose (FDG). Tracer accumulations in the tumours were then analysed and compared with the proliferation activity and apoptotic index of the tumours. In a separate cell study, 22Rv1 cells were treated with DTX, then incubated with FLT or FDG and examined for their tracer uptake. RESULTS: The microPET imaging showed a significant decrease of FLT uptake in tumours after administration of DTX, while the changes of FDG uptake were minimal. Immunohistochemical analysis of the tumours revealed that the changes of FLT uptake were well correlated with those of proliferation activity but not with the apoptotic index. In vitro studies demonstrated that the significant decrease of FLT uptake in the cells after incubation with DTX correlated with the % S-phase cell fraction, while there were only minimal changes in the prostate-specific antigen concentration of the cell medium and FDG uptake in the cells. CONCLUSION: These results indicate that FLT is a promising tracer for monitoring the early effects of anticancer therapy with DTX in patients with HRPC.

Potentiation of abnormalities in myocardial metabolism with the development of diabetes in women with obesity and insulin resistance.

BACKGROUND: Because studies in animal models of type-2 diabetes mellitus (DM) show that excessive myocardial fatty acid (FA) metabolism (at the expense of glucose metabolism) cause cardiac dysfunction, we hypothesized that women with DM would have more FA and less glucose myocardial metabolism than normal or even obese (OB) women. RESEARCH DESIGN AND METHODS: Women who were lean volunteers (NV) (N = 14; age 35 ± 17 years, body mass index 23 ± 1 kg/m(2)), OB (N = 28;31 ± 6 years, BMI 39 ± 7 kg/m2), and DM (n = 22; 54 ± 11 years, BMI 38 ± 5 kg/m2) were studied. Cardiac positron emission tomography was performed for the determination of myocardial blood flow, oxygen consumption, FA and glucose metabolism. Cardiac work was measured by echocardiography and efficiency by the ratio of work to myocardial oxygen consumption. RESULTS: Fractional glucose uptake was comparable between NV and OB but lower in DM (P < .05 versus NV). Myocardial FA utilization and oxidation were both higher in DM compared with NV and OB (P < .0001). Myocardial FA utilization and oxidation had positive correlations with HOMA (R = 0.35, P = .005 and R = 0.40, P = .001, respectively) whereas fractional glucose uptake exhibited an inverse correlation (R = -.31, P = .01). Cardiac work and efficiency were similar among the three groups. CONCLUSIONS: In women, the presence of OB and DM compared with OB alone is associated with a greater reliance on myocardial FA metabolism at the expense of glucose metabolism. These perturbations in myocardial metabolism are not associated in a decline left ventricular efficiency or function suggesting that the metabolic perturbations may precede an eventual decline left ventricular function as is seen in animal models of DM.

Development of [F-18]fluorine-substituted Tanaproget as a progesterone receptor imaging agent for positron emission tomography.

The level of progesterone receptors (PRs) in breast tumors can be used to guide the selection of endocrine therapies for breast cancer patients. To this end, we have prepared a fluorine-18 labeled analogue of Tanaproget, a nonsteroidal progestin with very high PR binding affinity and low affinity for androgen and glucocorticoid receptors, and have studied its tissue distribution in estrogen-primed rats to evaluate its potential for imaging PR levels by positron emission tomography. 4-[(18)F]Fluoropropyl-Tanaproget ([(18)F]9, FPTP) was prepared in three steps, within 140 min at an overall decay-corrected yield of 5% and effective specific activity of >550 Ci/mmol. In biodistribution studies, [(18)F]9 uptake was high in target tissues at both 1 and 3 h (uterus, 4.55 and 5.26%ID/g; ovary, 2.32 and 2.20%ID/g, respectively) and was cleanly blocked by coinjection of excess unlabeled compound. Uterus to blood and muscle activity ratios were 9.2 and 5.2 at 1 h and 32 and 26 at 3 h, respectively. The biodistribution of [(18)F]9 compares favorably to that of previously prepared F-18 labeled steroidal progestins, FENP and FFNP. Its high target tissue uptake efficiency and selectivity, and prolonged retention, suggest that it has excellent promise as a PET imaging agent for PR-positive breast tumors.

Synthesis and evaluation of 15-(4-(2-[¹8F]Fluoroethoxy)phenyl)pentadecanoic acid: a potential PET tracer for studying myocardial fatty acid metabolism.

15-(4-(2-[¹8F]fluoroethoxy)phenyl)pentadecanoic acid ([¹8F]7) was synthesized as a PET probe for assessing myocardial fatty acid metabolism. The radiosynthesis of [¹8F]7 was accomplished using a two-step reaction, starting with the corresponding tosylate ester, methyl 15-(4-(2-(tosyloxy)ethoxy)phenyl)pentadecanoate (5), and gave the radiolabeled fatty acid, [¹8F]7 in a radiolabeling yield of 55-60% and a specific activity of >2000 Ci/mmol (decay corrected to EOB). The biological evaluation of [¹8F]7 in rats displayed high uptake in heart (1.94%ID/g at 5 min), which was higher than the uptake (%ID/g) in blood, lung, muscle, pancreas, and brain. MicroPET studies of [¹8F]7 in Sprague-Dawley rats demonstrated excellent images of the myocardium when compared with [¹¹C]palmitate images in the same animal. Moreover, the tracer kinetics of [¹8F]7 paralleled those seen with [¹¹C]palmitate, with an early peak followed by biphasic washout. When compared to [¹¹C]palmitate, [¹8F]7 exhibited a slower early clearance (0.17 ± 0.01 vs 0.30 ± 0.02, P < 0.0001) and a significantly higher late clearance (0.0030 ± 0.0005 vs 0.0006 ± 0.00013, P < 0.01). These initial studies suggest that [¹8F]7 could be a potentially useful clinical PET tracer to assess abnormal myocardial fatty acid metabolism.

Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-gamma ligands: potential positron emission tomography imaging agents.

INTRODUCTION: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is an important regulator of lipid metabolism; it controls the differentiation of preadipocytes and is also found at high levels in small metastatic tumors. In this report, we describe the radiochemical synthesis and evaluation of two (18)F-labeled analogs of the potent and selective PPARgamma agonist farglitazar. MATERIALS AND METHODS: The isomeric aromatic fluorine-substituted target compounds [(2S)-(2-benzoylphenylamino)-3-(4-(2-[2-(4-[(18)F]fluorophenyl)-5-methyloxazol-4-yl]ethoxy)-phenyl)propionic acid ([(18)F]-1) and (2S)-[2-(4-fluorobenzoyl)phenylamino]-3-(4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenyl)propionic acid ([(18)F]-2)] were prepared in fluorine-18-labeled form, respectively, by radiofluorination of an iodonium salt precursor or by Ullmann-type condensation with 2-iodo-4'-[(18)F]fluorobenzophenone after nucleophilic aromatic substitution with [(18)F]fluoride ion. Each compound was obtained in high specific activity and good radiochemical yield. RESULTS AND DISCUSSION: (18)F-1 and (18)F-2 have high and selective PPARgamma binding affinities comparable to that of the parent molecule farglitazar, and they were found to have good metabolic stability. Tissue biodistribution studies of (18)F-1 and (18)F-2 were conducted, but PPARgamma-mediated uptake of both agents was minimal. CONCLUSION: This study completes our first look at an important class of PPARgamma ligands as potential positron emission tomography (PET) imaging agents for breast cancer and vascular disease. Although (18)F-1 and (18)F-2 have high affinities for PPARgamma and good metabolic stability, their poor target-tissue distribution properties, which likely reflect their high lipophilicity combined with the low titer of PPARgamma in target tissues, indicate that they have limited potential as PPARgamma PET imaging agents.

Assessment of myocardial triglyceride oxidation with PET and 11C-palmitate.

BACKGROUND: The goal of this study was to test whether myocardial triglyceride (TG) turnover including oxidation of TG-derived fatty acids (FA) could be assessed with PET and (11)C-palmitate. METHODS AND RESULTS: A total of 26 dogs were studied fasted (FAST), during Intralipid infusion (IL), during a hyperinsulinemic-euglycemic clamp without (HIEG), or with Intralipid infusion (HIEG + IL). (11)C-palmitate was injected, and 45 minutes were allowed for labeling of myocardial TG pool. 3D PET data were then acquired for 60 minutes, with first 15 minutes at baseline followed by 45 minutes during cardiac work stimulated with constant infusion of either phenylephrine (FAST, n = 6; IL, n = 6; HIEG + IL, n = 6) or dobutamine (FAST, n = 4; HIEG, n = 4). Myocardial (11)C washout during adrenergic stimulation (AS) was fitted to a mono-exponential function (Km(PET)). To determine the source of this (11)C clearance, Km(PET) was compared to direct coronary sinus-arterial measurements of total (11)C activity, (11)C-palmitate, and (11)CO(2). Before AS, PET curves in all groups were flat indicating absence of net clearance of (11)C activity from heart. In both FAST groups, AS resulted in negligible net (11)C activity and (11)CO(2) production higher than net (11)C-palmitate uptake. AS with phenylephrine resulted in net myocardial uptake of total (11)C activity and (11)C-palmitate in IL and HIEG + IL, and (11)CO(2) production lower than (11)C-palmitate uptake. In contrast, AS with dobutamine in HIEG resulted in net clearance of all (11)C metabolites (total (11)C activity, (11)C-palmitate and (11)CO(2)) with (11)CO(2) contributing 66% to endogenous FA oxidation. The AS resulted in significant Km(PET) in all the groups, except HIEG + IL. However, positive correlation between Km(PET) and (11)CO(2) was observed only in HIEG (R (2) = 0.83, P = .09). CONCLUSIONS: This is the first study to demonstrate that using PET and pre-labeling of intracardiac TG pool with (11)C-palmitate, noninvasive assessment of myocardial TG use is feasible under metabolic conditions that favor endogenous TG use such as increased metabolic demand (beta-adrenergic stimulation of cardiac work) with limited availability of exogenous substrate (HIEG).

Measurement of myocardial fatty acid esterification using [1-11C]palmitate and PET: comparison with direct measurements of myocardial triglyceride synthesis.

BACKGROUND: The purpose of the present study was to assess the accuracy of rates of myocardial fatty acid esterification (MFAE) obtained using positron emission tomography (PET). METHODS AND RESULTS: Sixteen dogs were studied after an overnight fast (FAST), during a euglycemic hyperinsulinemic clamp (CLAMP), or during infusion of intralipid (IL) or IL plus dobutamine (IL/DOB). MFAE was quantified using [1-(11)C]palmitate and PET and compared to the rate of triglyceride (TG) synthesis measured using [1-(13)C]palmitate and tissue sampling. Plasma free fatty acid (FFA) concentration varied approximately 20-fold across groups, with this variation in FFA availability accompanied by a approximately 20-fold range in TG synthesis. MFAE varied approximately 12-fold across groups, and was significantly correlated with TG synthesis (R = 0.80, P < .001). MFAE, however, was 3- to 4-fold higher than TG synthesis in FAST, CLAMP, and IL, but only approximately 50% higher when cardiac work was increased in IL/DOB, suggesting that MFAE reflects, in part, the incorporation of label into amino acids via TCA cycle exchange reactions. CONCLUSIONS: Changes in MFAE parallel changes in TG synthesis, at least in the basal state. Although the data need to be interpreted cautiously, such measurements should be useful for quantifying acute changes in FFA storage by the heart in various pathophysiological states.

7alpha-18F-fluoromethyl-dihydrotestosterone and 7alpha-18F-fluoromethyl-nortestosterone: ligands to determine the role of sex hormone-binding globulin for steroidal radiopharmaceuticals.

UNLABELLED: Sex hormone-binding globulin (SHBG) is believed to play a key role in steroidal radiopharmaceutical delivery to target tissues in humans. To better understand the action of SHBG, we have synthesized and tested in vivo 2 novel 18F-labeled androgens: 7alpha-18F-fluoromethyl-dihydrotestosterone (7alpha-18F-FM-DHT) and 7alpha-18F-fluoromethyl-nortestosterone (7alpha-18F-FM-norT). Both 7alpha-18F-FM-DHT and 7alpha-18F-FM-norT have high affinity for the androgen receptor (AR); however, 7alpha-18F-FM-DHT has a high affinity for SHBG, whereas 7alpha-18F-FM-norT has a relatively low affinity. METHODS: We developed an efficient radiochemical synthesis for both 7alpha-18F-FM-DHT and 7alpha-18F-FM-norT, producing them in good radiochemical yield and high specific activity. Biodistribution studies of both compounds were done on diethylstilbestrol-pretreated and DHT-blocked Sprague-Dawley male rats. Metabolism studies were done to determine the amount of intact ligand in the prostate. RESULTS: We obtained 7alpha-18F-FM-DHT and 7alpha-18F-FM-norT in radiochemical yields of about 30% and radiochemical purities of greater than 99%. Rat biodistribution studies showed selective AR-mediated uptake in the prostate for both compounds. Both compounds showed relatively little defluorination, but the norT analog was more metabolically stable than the DHT analog. CONCLUSION: These studies show that 7alpha-18F-FM-DHT and 7alpha-18F-FM-norT have potential for use in human clinical imaging trials to evaluate more definitively the role of SHBG in radiotracer delivery of steroidal systems to target tissues.

Autoradiographic and small-animal PET comparisons between (18)F-FMISO, (18)F-FDG, (18)F-FLT and the hypoxic selective (64)Cu-ATSM in a rodent model of cancer.

INTRODUCTION: Copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone), or Cu-ATSM, a hypoxia imaging agent, has been shown to be predictive of response to traditional cancer therapies in patients with a wide range of tumors. It is known that the environment of the tumor results in a myriad of physiological consequences, including hypoxia, alterations in metabolism and proliferation. In an effort to better characterize the relationships between Cu-ATSM and other prominent radiopharmaceuticals, this current study was undertaken to compare the regional distribution of (64)Cu-ATSM with [(18)F]fluoromisonidazole ((18)F-FMISO), [(18)F]fluoro-2-deoxy-d-glucose ((18)F-FDG) and [(18)F]fluorothymidine ((18)F-FLT) in 9L tumors. METHODS: Taking advantage of the different half-life of (18)F (t(1/2)=110 min) in comparison to (64)Cu (t(1/2)=12.7 h), we undertook a dual-tracer autoradiography study in 9L tumors. Four groups were examined: (a) (18)F-FMISO, 2 h postinjection (p.i.) and (64)Cu-ATSM, 10 min p.i.; (b) (18)F-FMISO, 2 h p.i. and (64)Cu-ATSM, 24 h p.i.; (c) (18)F-FDG, 1 h p.i. and (64)Cu-ATSM, 10 min p.i.; and (d) (18)F-FLT, 1 h p.i. and (64)Cu-ATSM, 10 min p.i. Small-animal PET imaging was performed in 9L tumor-bearing rats with imaging on concurrent days comparing (64)Cu-ATSM with (18)F-FMISO and (18)F-FLT. RESULTS: It was shown that the regional distribution of (18)F-FMISO and (64)Cu-ATSM showed an excellent correlation when the (64)Cu-ATSM had been allowed to distribute for either 10 min (R(2)=.84) or 24 h (R(2)=.86). The regional comparisons between (64)Cu-ATSM (10 min) and (18)F-FDG (1 h) resulted in a very poor correlation (R(2)=.08) between the regional uptake of the two agents. The comparison between (18)F-FLT and (64)Cu-ATSM showed a strong relationship (R(2)=.83) between the two tracers. The small-animal PET images for the distribution comparisons between (64)Cu-ATSM and (18)F-FMISO and (18)F-FLT were in agreement with the data generated from the autoradiography studies. CONCLUSIONS: The data show that it is important to remember that a number of different metabolic situations can exist when considering the relationship between regions of high glucose uptake, proliferation and hypoxia.

PET detection of the impact of dobutamine on myocardial glucose metabolism in women with type 1 diabetes mellitus.

BACKGROUND: Our objective was to determine, in the hearts of women with type 1 diabetes mellitus (T1DM), whether the fate of extracted glucose is altered and, if so, what the impact of dobutamine is on myocardial substrate metabolism. In experimental models of T1DM, myocardial glycolysis and glucose oxidation are reduced with the impairment becoming more pronounced with dobutamine. Whether similar changes occur in humans with T1DM is unclear. METHODS AND RESULTS: Myocardial perfusion, oxygen consumption, and glucose and fatty acid metabolism were measured with positron emission tomography in 19 women, 7 normal volunteers (NVs) and 12 with T1DM. The NVs and 6 T1DM (DM1) patients were studied under baseline metabolic conditions and 6 T1DM patients were studied during hyperinsulinemic-euglycemic clamp (DM1-C), both at rest and during dobutamine. At rest, myocardial glucose uptake, glycolysis, glycogen storage, and oxidation were reduced by similar levels in DM1 patients compared with NVs (P < .05). During dobutamine, although myocardial glucose uptake was not different from DM1 patients at rest, fractional glycolysis was lower compared with NVs or DM1-C patients and reflected a lower glucose oxidation rate (P < .001). Measurements of myocardial glucose metabolism at rest and during dobutamine were comparable between NVs and DM1-C patients. During dobutamine, myocardial fatty acid uptake and oxidation increased in all 3 groups. CONCLUSIONS: In women with T1DM, (1) myocardial glucose metabolism is impaired downstream from initial uptake, (2) these abnormalities become more pronounced with dobutamine and are paralleled by an increase in myocardial fatty acid metabolism, and (3) insulin restores glucose metabolism to levels observed in normal control subjects.

Synthesis and biological evaluation of [18F]bicalutamide, 4-[76Br]bromobicalutamide, and 4-[76Br]bromo-thiobicalutamide as non-steroidal androgens for prostate cancer imaging.

Androgen receptors (AR) are overexpressed in most primary and metastatic prostate cancers. To develop a nonsteroidal AR-mediated imaging agent, we synthesized and radiolabeled several analogs of the potent antiandrogen bicalutamide: [18F]bicalutamide, 4-[76Br]bromobicalutamide, and [76Br]bromo-thiobicalutamide. Two of these analogs, 4-[76Br]bromobicalutamide and [76Br]bromo-thiobicalutamide, were found to have a substantially increased affinity for the androgen receptor (AR) compared to that of bicalutamide. The synthesis of [18F]bicalutamide utilized a pseudocarrier approach to effect addition of a carbanion generated from tracer-level amounts of a radiolabeled precursor to an unlabeled carbonyl precursor. 4-[76Br]Bromobicalutamide and [76Br]bromo-thiobicalutamide were labeled through electrophilic bromination of a tributylstannane precursor. The former could be prepared in high specific activity, and its tissue distribution was tested in vivo. Androgen target tissue uptake was evident in castrated adult male rats; however, in DES-treated, AR-positive, tumor-bearing male mice, tumor uptake was low.

L-3-11C-lactate as a PET tracer of myocardial lactate metabolism: a feasibility study.

UNLABELLED: Lactate is a key myocardial energy source. Lactate metabolism is altered in a variety of conditions, such as exercise and diabetes mellitus. However, to our knowledge, noninvasive quantitative measurements of myocardial lactate metabolism have never been performed because of the lack of an adequate radiotracer. In this study we tested L-3-(11)C-lactate ((11)C-lactate) as such a tracer. METHODS: Twenty-three dogs were studied under a wide range of metabolic interventions. (11)C-Lactate and (13)C-lactate were injected as boluses and PET data were acquired for 1 h. Concomitant arterial and coronary sinus (ART/CS) blood samples were collected to identify (13)C-lactate metabolites and to measure fractional myocardial extraction/production of (11)C metabolite fractions ((11)C acidic: (11)CO(2) and (11)C-lactate; (11)C basic: (11)C-labeled amino acids; and (11)C neutral: (11)C-glucose). Lactate metabolism was quantified using 2 PET approaches: monoexponential clearance analysis (oxidation only) and kinetic modeling of PET (11)C-myocardial curves. RESULTS: Arterial (11)C acidic, neutral, and basic metabolites were identified as primarily (11)C-labeled lactate + pyruvate, glucose, and alanine, respectively. Despite a significant contribution of (11)C-glucose (23%-45%) and (11)C-alanine (<11%) to total arterial (11)C activity, both were minimally extracted(+)/produced(-) by the heart (1.7% +/- 1.0% and -0.12% +/- 0.84%, respectively). Whereas extraction of (11)C-lactate correlated nonlinearly with that of unlabeled lactate extraction (r = 0.86, P < 0.0001), (11)CO(2) production correlated linearly with extraction of unlabeled lactate (r = 0.89, P < 0.0001, slope = 1.20 +/- 0.13). In studies with physiologic free fatty acids (FFA) (415 +/- 216 nmol/mL), (11)C-lactate was highly extracted (32% +/- 12%) and oxidized (26% +/- 14%), and PET monoexponential clearance and kinetic modeling analyses resulted in accurate estimates of lactate oxidation and metabolism. In contrast, supraphysiologic levels of plasma FFA (4,111 +/- 1,709 nmol/mL) led to poor PET estimates of lactate metabolism due to negligible lactate oxidation (1% +/- 2%) and complete backdiffusion of unmetabolized (11)C-lactate into the vasculature (28% +/- 22%). CONCLUSION: Under conditions of net lactate extraction, L-3-(11)C-lactate faithfully traces myocardial metabolism of exogenous lactate. Furthermore, in physiologic substrate environments, noninvasive measurements of lactate metabolism are feasible with PET using myocardial clearance analysis (oxidation) or compartmental modeling. Thus, L-3-(11)C-lactate should prove quite useful in widening our understanding of the role that lactate oxidation plays in the heart and other tissues and organs.

18F-fluoroacetate: a potential acetate analog for prostate tumor imaging--in vivo evaluation of 18F-fluoroacetate versus 11C-acetate.

UNLABELLED: PET with (11)C-acetate ((11)C-ACE) has a high sensitivity for detection of prostate cancer and several other cancers that are poorly detected with (18)F-FDG. However, the short half-life (20.4 min) of (11)C limits the general availability of (11)C-ACE. (18)F-Fluoroacetate ((18)F-FAC) is an analog of acetate with a longer radioactive half-life ((18)F = 110 min). This study was undertaken to assess the potential usefulness of (18)F-FAC as a prostate tumor imaging agent. METHODS: We developed an efficient radiosynthesis for (18)F-FAC, which has already been adapted to a commercial synthesizer. Biodistribution studies of (18)F-FAC were compared with (11)C-ACE in normal Sprague-Dawley male rats and CWR22 tumor-bearing nu/nu mice. We also performed a small-animal PET study of (18)F-FAC in CWR22 tumor-bearing nu/nu mice and a whole-body PET study in a baboon to examine defluorination. RESULTS: We obtained (18)F-FAC in a radiochemical yield of 55% +/- 5% (mean +/- SD) in approximately 35 min and with a radiochemical purity of >99%. Rat biodistribution showed extensive defluorination, which was not observed in the baboon PET, as indicated by the standardized uptake values (SUVs) (SUVs of iliac bones and femurs were 0.26 and 0.3 at 1 h and 0.22 and 0.4 at 2 h, respectively). CWR22 tumor-bearing nu/nu mice showed tumor uptake (mean +/- SD) of 0.78 +/- 0.06 %ID/g (injected dose per gram of tissue) for (11)C-ACE versus 4.01 +/- 0.32 %ID/g for (18)F-FAC. For most organs-except blood, muscle, and fat-the tumor-to-organ ratios at 30 min after injection were higher with (18)F-FAC, whereas the tumor-to-heart and tumor-to-prostate ratios were similar. CONCLUSION: All of these data indicate that (18)F-FAC may be a useful alternative to (11)C-ACE tracer for the detection of prostate tumors by PET.

PET measurements of myocardial glucose metabolism with 1-11C-glucose and kinetic modeling.

UNLABELLED: The aim of this study was to investigate whether compartmental modeling of 1-(11)C-glucose PET kinetics can be used for noninvasive measurements of myocardial glucose metabolism beyond its initial extraction. METHODS: 1-(11)C-Glucose and U-(13)C-glucose were injected simultaneously into 22 mongrel dogs under a wide range of metabolic states; this was followed by 1 h of PET data acquisition. Heart tissue samples were analyzed for (13)C-glycogen content (nmol/g). Arterial and coronary sinus blood samples (ART/CS) were analyzed for glucose (mumol/mL), (11)C-glucose, (11)CO(2), and (11)C-total acidic metabolites ((11)C-lactate [LA] + (11)CO(2)) (counts/min/mL) and were used to calculate myocardial fractions of (a) glucose and 1-(11)C-glucose extractions, EF(GLU) and EF((11)C-GLU); (b) (11)C-GLU and (11)C-LA oxidation, OF((11)C-GLU) and OF((11)C-LA); (c) (11)C-glycolsysis, GCF((11)C-GLU); and (d) (11)C-glycogen content, GNF((11)C-GLU). On the basis of these measurements, a compartmental model (M) that accounts for the contribution of exogenous (11)C-LA to myocardial (11)C activity was implemented to measure M-EF(GLU), M-GCF(GLU), M-OF(GLU), M-GNF(GLU), and the fraction of myocardial glucose stored as glycogen M-GNF(GLU)/M-EF(GLU)). RESULTS: ART/CS data showed the following: (a) A strong correlation was found between EF((11)C-GLU) and EF(GLU) (r = 0.92, P < 0.0001; slope = 0.95, P = not significantly different from 1). (b) In interventions with high glucose extraction and oxidation, the contribution of OF((11)C-GLU) to total oxidation was higher than that of OF((11)C-LA) (P < 0.01). In contrast, in interventions in which glucose uptake and oxidation were inhibited, OF((11)C-LA) was higher than OF((11)C-GLU) (P < 0.05). (c) A strong correlation was found between GNF((11)C-GLU)/EF(GLU) and direct measurements of fractional (13)C-glycogen content, (r = 0.96, P < 0.0001). Model-derived PET measurements of M-EF(GLU), M-GCF(GLU), and M-OF(GLU) strongly correlated with EF(GLU) (slope = 0.92, r = 0.95, P < 0.0001), GCF((11)C-GLU) (slope = 0.79, r = 0.97, P < 0.0001), and OF((11)C-GLU) (slope = 0.70, r = 0.96, P < 0.0001), respectively. M-GNF(GLU)/M-EF(GLU) strongly correlated with fractional (13)C-content (r = 0.92, P < 0.0001). CONCLUSION: Under nonischemic conditions, it is feasible to measure myocardial glucose metabolism noninvasively beyond its initial extraction with PET using 1-(11)C-glucose and a compartmental modeling approach that takes into account uptake and oxidation of secondarily labeled exogenous (11)C-lactate.

Synthesis and biodistribution of fluorine-18-labeled fluorocyclofenils for imaging the estrogen receptor.

C4-[18F]Fluorocyclofenil ([18F]FCF, 6) and C3-[18F]fluoroethylcyclofenil ([18F]FECF, 9), two high-affinity nonsteroidal estrogens, were prepared and investigated as potential agents for imaging estrogen receptors (ERs) in breast tumors. Both of these compounds could be prepared conveniently from alkyl methanesulfonate precursors (5,8) by fluoride displacement reactions, and they were obtained in high radiochemical purity and radiochemical yields, with effective specific activities sufficient for in vivo biodistribution studies. While the biodistribution of [18F]FCF (6) in immature female rats showed no selective target tissue uptake, the biodistribution of [18F]FECF (9) showed selective uptake by the uterus, but this uptake could not be blocked by excess estradiol. The poor in vivo biodistribution of these otherwise high-affinity ligands arouses curiosity, and together with recent results on the biodistribution of other nonsteroidal ligands suggests that factors other than receptor binding affinity are important for in vivo imaging of estrogen target tissues and ER-positive breast tumors.

Sex differences in myocardial oxygen and glucose metabolism.

BACKGROUND: Both physiologic and pathophysiologic conditions affect the myocardium's substrate use and, consequently, its structure, function, and adaptability. The effect of sex on myocardial oxygen, glucose, and fatty acid metabolism in humans is unknown. METHODS AND RESULTS: We studied 25 young subjects (13 women and 12 men) using positron emission tomography, quantifying myocardial blood flow, myocardial oxygen consumption (MVO2), and glucose and fatty acid extraction and metabolism. MVO2 was higher in women than in men (5.74 +/- 1.08 micromol x g(-1) x min(-1) vs 4.26 +/- 0.69 micromol x g(-1) x min(-1), P < .005). Myocardial glucose extraction fraction and utilization were lower in women than in men (0.025 +/- 0.019 vs 0.062 +/- 0.028 [P < .001] and 133 +/- 96 nmol x g(-1) x min(-1) vs 287 +/- 164 nmol x g(-1) x min(-1) [P < .01], respectively). There were no sex differences in myocardial blood flow, fatty acid metabolism, or plasma glucose, fatty acid, or insulin levels. Female sex was an independent predictor of increased MVO2 (P = .01) and decreased myocardial glucose extraction fraction and utilization (P < .005 and P < .05, respectively). Insulin sensitivity was an independent predictor of increased myocardial glucose extraction fraction and utilization (P < .01 and P = .01, respectively). CONCLUSIONS: Further studies are necessary to elucidate the mechanisms responsible for sex-associated differences in myocardial metabolism. However, the presence of such differences may provide a partial explanation for the observed sex-related differences in the prevalence and manifestation of a variety of cardiac disorders.