(2R)-2-4-(6-fluorohex-1-ynyl)phenylsulfonylamino-3-methylbutyric acid
11Cmethyl ester (
11CFMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for ...evaluation as new potential positron emission tomography (PET) cancer biomarker.
11CFMAME was prepared by appropriate precursor (2R)-2-4-(6-fluorohex-1-ynyl)phenylsulfonylamino-3-methylbutyric acid (FMA), which was synthesized in six steps from (D)-valine in 71% chemical yield. This acid precursor was labeled by
11Cmethyl triflate through O-
11Cmethylation method under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compound in 40-55% radiochemical yield, based on
11CO
2, decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of
11CFMAME was determined at 30 min post IV injection in breast cancer animal models MCF-7 transfected with IL-1α implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of
11CFMAME in these tumors were 1.13% dose/g in MCF-7 transfected with IL-1α implanted mice and 1.37% dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.05 ± 0.29 (T/M, MCF-7’s), 0.77 ± 0.20 (T/B, MCF-7’s) and 0.99 ± 0.35 (T/M, MDA-MB-435), 1.44 ± 0.69 (T/B, MDA-MB-435), respectively. Pretreatment of MCF-7 transfected with IL-1α tumor-bearing mice with MMP inhibitor FMA had no effect on
11CFMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on
11CFMAME biodistribution. The micro-PET images were acquired for 15 min from a MCF-7 transfected with IL-1α tumor-bearing mouse or a MDA-MB-435 tumor-bearing mouse at 30 min post IV injection of 1 mCi of
11CFMAME using a dedicated high resolution (<3 mm full-width at half-maximum) PET imaging system (Indy-PET II scanner). The initial dynamic micro-PET images of
11CFMAME in a MCF-7 transfected with IL-1α tumor-bearing mouse during different time periods of 0-15, 15-30, 30-45 and 45-60 min were performed by Indy-PET II. The PET images clearly showed both tumors were visible with
11CFMAME. These results suggest that the localization of
11CFMAME in the tumor is mediated by non-specific processes, and the visualization of
11CFMAME on the tumor using the Indy-PET II scanner is related to non-specific binding.
(S)-2-(4′-
11Cmethoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid (
11CMSMA) and N-hydroxy-(R)-2-(4′-
11Cmethoxyphenyl)sulfonylbenzylamino-3-methylbutanamide (
11CCGS 25966), carbon-11 labeled ...matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarkers.
11CMSMA was prepared by appropriate precursor (S)-2-(4′-hydroxybiphenyl-4-sulfonylamino)-3-methylbutyric acid
tert-butyl ester, which was synthesized in eight steps from amino acid (L)-valine in 39.4% chemical yield. This precursor was labeled by
11Cmethyl triflate through O-
11Cmethylation method at the hydroxyl position of biphenol under basic conditions, followed by a quick acid hydrolysis and isolated by solid-phase extraction (SPE) purification to produce pure target compound
11CMSMA in 35-55% radiochemical yield, based on
11CO
2, decay corrected to end of bombardment (EOB), and 20-25 min synthesis time.
11CCGS 25966 was prepared in our previous work starting from amino acid (D)-valine. The biodistribution of
11CMSMA and
11CCGS 25966 were determined at 45 min post iv injection in breast cancer animal models MCF-7's transfected with IL-1α implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of
11CMSMA and
11CCGS 25966 in these tumors were 0.95 and 0.42%dose/g in MCF-7's transfected with IL-1α implanted mice, 0.98 and 1.53%dose/g in MDA-MB-435 implanted mice, respectively; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.21 and 1.09 (T/M, MCF-7's), 0.99 and 0.84 (T/B, MCF-7's), 1.38 and 1.27 (T/M, MDA-MB-435), 1.27 and 1.95 (T/B, MDA-MB-435), respectively. The micro-PET images of
11CMSMA and
11CCGS 25966 in both breast cancer athymic mice were acquired for 15 min from a MCF-7's transfected with IL-1α and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our laboratory, which showed both tumors were invisible with both tracers. The results were compared. From our results, we concluded that both
11CMSMA and
11CCGS 25966 might be unsuitable as PET tracers for cancer imaging.
Correlates of Attributing New Disability to Old Age Sarkisian, Catherine A.; Liu, Honghu; Ensrud, Kristine E. ...
Journal of the American Geriatrics Society (JAGS),
Febuary 2001, Letnik:
49, Številka:
2
Journal Article
Recenzirano
Odprti dostop
OBJECTIVES: To describe women who attribute new disability to old age and to identify demographic, medical, behavioral, and psychosocial characteristics that correlate with attributing new disability ...to old age.
DESIGN: Prospective cohort study with 4‐year follow‐up.
SETTING: Four geographic regions of the United States.
PARTICIPANTS: 9704 women aged ≥67 years participating in the Study of Osteoporotic Fractures. Of these, 657 who reported no disability at baseline but at follow‐up reported difficulty carrying out 1 or more of 13 functional activities were eligible for our analysis.
MEASUREMENTS: All women reporting difficulty in any functional activity at follow‐up were asked “What is the main condition that causes you to have difficulty or prevents you from (doing the activity)?” and were shown a card listing 14 medical conditions as well as the option “old age,” from which they could choose only one response. Women attributing difficulty or inability in 1 or more functional activities to old age were classified as attributing new disability to old age. We examined the relationship between attributing new disability to old age and the following characteristics measured at baseline: age, level of education, medical comorbidity, cognitive function, body mass index (BMI), gait speed, grip strength, visual acuity, physical activity level, smoking status, social network level, and depressed mood.
RESULTS: Overall, 13.5% of women attributed new disability to old age. Age was a strong independent correlate of attributing new disability to old age: compared with women age 67 to 69, the odds of attributing new disability to old age for women age 70 to 79 was 3.6 times as large (95% confidence interval CI = 1.6–8.3), and for women age 80 or over was 5.5 times as large (95% CI = 2.1–14.7). The only other characteristic that remained an independent correlate of attributing new disability to old age was grip strength; for each decile decrease in grip strength, a woman's odds of attributing new disability to old age increased by 9% (odds ratio OR = 1.09, 95% CI = 1.01–1.19).
CONCLUSIONS: Despite great advances in geriatric medicine, old age is still perceived as a causal agent in functional decline, especially among our oldest patients. Further study is needed to determine whether, how often, and under what circumstances older adults who attribute new disability to old age have medical conditions amenable to interventions that could preserve their functioning and improve their quality of life.
To investigate breast cancer risk according to metabolizing genes polymorphisms in older women.
A subset (43.8%) of 4248 older, white women from the Study of Osteoporotic Fractures (SOF) were ...genotyped for the catechol-O-methyltransferase (COMT) Val108Met polymorphism and the CYP1A1*2C locus. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between genotypes and breast cancer while controlling for potential confounders.
During a mean follow up of 12.4 years, 252 women (5.9%) developed breast cancer. The HR (95% CI) for breast cancer was 1.24 (0.87-1.75) for COMT(Val/Met) and 1.35 (0.93-1.97) for COMT(Met/Met). No interactions with lifestyle and reproductive factors were found. The HR associated with the CYP1A1*2C Val allele was 0.80 (0.46, 1.39) with little evidence for interactions with lifestyle or reproductive factors.
Among older white women, neither the COMT Val108/158Met polymorphism nor the CYP1A*2C Val allele plays a major role in breast cancer risk either alone or in combination with lifestyle and reproductive factors.
Three sites of N G,N G-arginine methylation have been located at residues 205, 217, and 224 in the glycine-rich, COOH-terminal one-third of the HeLa A1 heterogeneous ribonucleoprotein. Together with ...the previously determined dimethylated arginine at position 193 Williams et al., (1985) Proc. Natl. Acad. Sci. U. S.A. 82, 5666−5670, it is evident that all four sites fall within a span of sequence between residues 190 and 233 that contains multiple Arg-Gly-(Gly) sequences interspersed with phenylalanine residues. These RGG boxes have been postulated to represent an RNA binding motif Kiledjian and Dreyfuss (1992) EMBO J. 11, 2655−2664. Dimethylation of HeLa A1 appears to be quantitative at each of the four positions. Arginines 205 and 224 have been methylated in vitro by a nuclear protein arginine methyltransferase using recombinant (unmethylated) A1 as substrate. This suggests A1 may be an in vivo substrate for this enzyme. Examination of sequences surrounding the sites of methylation in A1 along with a compilation from the literature of sites that have been identified in other nuclear RNA binding proteins suggests a methylase-preferred recognition sequence of Phe/Gly-Gly-Gly-Arg-Gly-Gly-Gly/Phe, with the COOH-terminal flanking glycine being obligatory. Taken together with data in the literature, identification of the sites of A1 arginine methylation strongly suggests a role for this modification in modulating the interaction of A1 with nucleic acids.
11CCholine has been evaluated as a potential positron emission tomography (PET) marker for imaging of breast cancer. The biodistribution of
11Ccholine was determined at 45 min post iv injection in ...MCF-7’s transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptake of
11Ccholine in these tumors was high, 2.0% dose/g in MCF-7’s transfected with IL-1alpha implanted mice and 1.8% dose/g in MDA-MB-435 implanted mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 1.7 (T/M, MCF-7’s), 2.1 (T/M, MDA-MB-435) and 6.9 (T/B, MCF-7’s), 12.5 (T/B, MDA-MB-435), respectively; the tumor/muscle ratios are moderate, and the tumor/blood ratios are high. The micro-PET imaging of
11Ccholine in both breast cancer athymic mice was acquired for 15 min from a MCF-7’s transfected with IL-1alpha and/or MDA-MB-435 implanted mouse at 45 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, Indy-PET II scanner, developed in our laboratory, which showed the uptake of
11Ccholine in MCF-7’s transfected with IL-1alpha tumor or MDA-MB-435 tumor implanted in a nude athymic mouse. These results suggest that
11Ccholine may be a potential PET breast cancer imaging agent.
Novel radiolabeled O
6-benzylguanine (O
6-BG) derivatives, 2-amino-6-O-
11C-(methoxymethyl)benzyloxy-9-methyl purines (
11C
p-O
6-AMMP,
1a;
11C
m-O
6-AMMP,
1b;
11C
o-O
6-AMMP,
1c), ...2-amino-6-O-benzyloxy-9-
11C-(methoxycarbonyl)methylpurine (
11CABMMP,
2), and 2-amino-6-O-benzyloxy-9-
11C-(4′-methoxycarbonyl)benzylpurine (
11CABMBP,
3), have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for the DNA repair protein O
6-alkylguanine-DNA alkyltransferase (AGT) in breast cancer. The appropriate precursors for radiolabeling were obtained in two to three steps from starting material 2-amino-6-chloropurine with moderate to excellent chemical yields. Tracers were prepared by O-
11Cmethylation of hydroxymethyl or acid precursors using
11Cmethyl triflate. Pure target compounds were isolated by solid-phase extraction (SPE) purification procedure in 45–65% radiochemical yields (decay corrected to end of bombardment), and a synthesis time of 20–25 min. The activity of unlabeled standard samples of
1–3 was evaluated via an
in vitro AGT oligonucleotide assay. Preliminary findings from biological assay indicate the synthesized analogs have similar strong inhibitory effectiveness on AGT in comparison with the parent compound O
6-BG. The results warrant further evaluation of these radiotracers as new potential PET imaging agents for the DNA repair protein AGT in breast cancer
in vivo.
Radiolabeled antimitotic agents 11CT138067 and 18FT138067 have been synthesized for evaluation as new potential positron emission tomography (PET) biomarkers for cancer imaging. In vivo ...biodistribution and micro-PET imaging of 11CT138067 were performed in breast cancer animal models MCF-7 transfected with IL-1alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results suggest that the uptakes of 11CT138067 in both MCF-7 transfected with IL-1alpha tumor and MDA-MB-435 tumor are non-specific binding.
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