Xiangshu Fei

Synthesis and preliminary biological evaluation of MMP inhibitor radiotracers [11C]methyl-halo-CGS 27023A analogs, new potential PET breast cancer imaging agents

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.

Synthesis, biodistribution and micro-PET imaging of a potential cancer biomarker carbon-11 labeled MMP inhibitor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [11C]methyl ester

(2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [(11)C]methyl ester ([(11)C]FMAME), a novel carbon-11 labeled matrix metalloproteinase (MMP) inhibitor, has been synthesized for evaluation as new potential positron emission tomography (PET) cancer biomarker. [(11)C]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 [(11)C]methyl triflate through O-[(11)C]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 (11)CO(2), decay corrected to end of bombardment, and 15-20 min synthesis time. The biodistribution of [(11)C]FMAME was determined at 30 min post IV injection in breast cancer animal models MCF-7 transfected with IL-1 alpha implanted athymic mice and MDA-MB-435 implanted athymic mice. The results showed the uptakes of [(11)C]FMAME in these tumors were 1.13% dose/g in MCF-7 transfected with IL-1 alpha 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-7s), 0.77 +/- 0.20 (T/B, MCF-7s) 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-1 alpha tumor-bearing mice with MMP inhibitor FMA had no effect on [(11)C]FMAME biodistribution. Likewise, pretreatment of MDA-MB-435 tumor-bearing mice with FMA also showed no effect on [(11)C]FMAME biodistribution. The micro-PET images were acquired for 15 min from a MCF-7 transfected with IL-1 alpha tumor-bearing mouse or a MDA-MB-435 tumor-bearing mouse at 30 min post IV injection of 1 mCi of [(11)C]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 [(11)C]FMAME in a MCF-7 transfected with IL-1 alpha 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 [(11)C]FMAME. These results suggest that the localization of [(11)C]FMAME in the tumor is mediated by non-specific processes, and the visualization of [(11)C]FMAME on the tumor using the Indy-PET II scanner is related to non-specific binding.

An improved synthesis of PET dopamine D2 receptors radioligand [11c]raclopride

Abstract An improved synthesis of [11C]raclopride is reported. The precursor desmethyl‐raclopride was synthesized from 3,5‐dichloro‐2,6‐dimethoxybenzoic acid and (S)‐(−)‐2‐aminoethyl‐1‐ethylpyrrolidine via a straightforward, four‐step synthetic approach with 29% overall chemical yield. [11C]Raclopride was prepared by O‐[11C]methylation of the precursor with [11C]methyl triflate and purification with a semi‐preparative HPLC method in 20–34% radiochemical yield, based on [11C]methyl bromide, decay corrected to end of bombardment (EOB).

Facile synthesis of [11C]edrophonium and its analogues as new potential PET imaging agents for heart acetylcholinesterase

[11C]Edrophonium and its analogues have been synthesized for evaluation as new potential positron emission tomography (PET) imaging agents for heart acetylcholinesterase. The tracers were prepared by N-[11C]methylation of precursors using [11C]methyl triflate and isolated by solid-phase extraction (SPE) purification procedure in 50-65% radiochemical yields.

Synthesis and preliminary biological evaluation of 6-O-[11C]-[(methoxymethyl)benzyl]guanines, new potential PET breast cancer imaging agents for the DNA repair protein AGT

Novel radiolabeled O(6)-benzylguanine derivatives, 6-O-[(11)C]-[(methoxymethyl)benzyl]guanines ([(11)C]p-O(6)-MMBG, 1a; [(11)C]m-O(6)-MMBG, 1b; ([(11)C]o-O(6)-MMBG, 1c), have been synthesized for evaluation as new potential positron emission tomography (PET) breast cancer imaging agents for DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase (AGT).

An improved total synthesis of PET HSV-tk gene expression imaging agent 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([18F]FHPG)

Abstract An improved total synthesis of [18F]FHPG starting from 1,3‐dibenzyloxy‐2‐propanol and guanine has been developed. [18F]FHPG was prepared by nucleophilic substitution of the appropriate precursor with [18F]KF/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with a simplified Silica Sep‐Pak solid‐phase extraction (SPE) method in 10–15% radiochemical yield, and 70 min synthesis time from end of bombardment (EOB).

An improved total synthesis of PET HSV-tk gene reporter probe 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine ([18F]FHBG)

Abstract An improved total synthesis of [18F]FHBG starting from triethyl‐1,1,2‐ethanetricarboxylate and 2‐amino‐6‐chloropurine is reported. [18F]FHBG was prepared by nucleophilic substitution of the appropriate precursor with [18F]KF/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with a simplified Silica Sep‐Pak solid‐phase extraction (SPE) method in 20–25% radiochemical yield.

A Convenient Procedure for the Synthesis of O6-Benzylguanine Derivatives by Phase Transfer Catalysis

Abstract A convenient procedure by phase transfer catalysis has been developed for the synthesis of O6-BG (1) and its derivatives hydroxymethyl-BG (2a–c), halo-BG (3a–c, 4a–c, 5a–c, 6a–c), methoxy-BG (7), and methyl-BG (8). Compounds 2b, 2c, 4b, 4c, 5b, 5c, 6a, and 6c are new compounds.