[en] Novel radiolabeled O⁶-benzylguanine (O⁶-BG) derivatives, 2-amino-6-O-[¹¹C]-[(methoxymethyl)benzyloxy]-9-methyl purines ([¹¹C]p-O⁶-AMMP, 1a; [¹¹C]m-O⁶-AMMP, 1b; [¹¹C]o-O⁶-AMMP, 1c), 2-amino-6-O-benzyloxy-9-[¹¹C]-[(methoxycarbonyl)methyl]purine ([¹¹C]ABMMP, 2), and 2-amino-6-O-benzyloxy-9-[¹¹C]-[(4'-methoxycarbonyl)benzyl]purine ([¹¹C]ABMBP, 3), have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for the DNA repair protein O⁶-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-[¹¹C]methylation of hydroxymethyl or acid precursors using [¹¹C]methyl 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 O⁶-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

[en] A series of [¹¹C]methyl-halo-CGS 27023A analogs (2-F, 1a; 4-F, 1b; 2-Cl, 1c; 3-Cl, 1d; 4-Cl, 1e; 2-Br, 1f; 3-Br, 1g; 4-Br, 1h; 4-I, 1i), novel radiolabeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents. The precursors halo-CGS 27023A analogs (2-F, 6a; 4-F, 6b; 2-Cl, 6c; 3-Cl, 6d; 4-Cl, 6e; 2-Br, 6f; 3-Br, 6g; 4-Br, 6h; 4-I, 6i) for radiolabeling were obtained in four steps from starting material amino acid D-valine with moderate to excellent chemical yields. Precursors were labeled by [¹¹C]methyl triflate through ¹¹C-O-methylation method at the aminohydroxyl position under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compounds in 40-60% radiochemical yields (decay corrected to end of bombardment), in 20-25 min synthesis time

[en] (S)-2-(4'-[¹¹C]methoxybiphenyl-4-sulfonylamino)-3-methylbutyric acid ([¹¹C]MSMA) and N-hydroxy-(R)-2-[[(4'-[¹¹C]methoxyphenyl)sulfonyl]benzylamino]-3- methylbutanamide ([¹¹C]CGS 25966), carbon-11 labeled matrix metalloproteinase (MMP) inhibitors, have been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarkers. [¹¹C]MSMA was prepared by appropriate precursory droxybiphenyl-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 [¹¹C]methyl triflate through O-[¹¹C]methylation 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 [¹¹C]MSMA in 35-55% radiochemical yield, based on ¹¹CO₂, decay corrected to end of bombardment (EOB), and 20-25 min synthesis time. [¹¹C]CGS 25966 was prepared in our previous work starting from amino acid (D)-valine. The biodistribution of [¹¹C]MSMA and [¹¹C]CGS 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 [¹¹C]MSMA and [¹¹C]CGS 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 [¹¹C]MSMA and [¹¹C]CGS 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 [¹¹C]MSMA and [¹¹C]CGS 25966 might be unsuitable as PET tracers for cancer imaging

[en] (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [¹¹C]methyl ester ([¹¹C]FMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarker. [¹¹C]FMAME was prepared by appropriate precursor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid (FMA), which was synthesized in six steps from (D)-valine in 71% chemical yield. This acid precursor was labeled by [¹¹C]methyl triflate through O-[¹¹C]methylation method under basic conditions and isolated by solid-phase extraction (SPE) purification to produce pure target compound in 40-55% radiochemical yield, based on ¹¹CO₂, decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of [¹¹C]FMAME 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 [¹¹C]FMAME 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 [¹¹C]FMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on [¹¹C]FMAME 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 [¹¹C]FMAME 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 [¹¹C]FMAME 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 [¹¹C]FMAME. These results suggest that the localization of [¹¹C]FMAME in the tumor is mediated by non-specific processes, and the visualization of [¹¹C]FMAME on the tumor using the Indy-PET II scanner is related to non-specific binding