Novel Fluorinated Derivatives of the Broad-Spectrum MMP Inhibitors N-Hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)- and (3-picolyl)-amino]-3-methyl-butanamide as Potential Tools for the Molecular Imaging of Activated MMPs with PET

Abstract

An approach to the in vivo imaging of locally upregulated and activated matrix metalloproteinases (MMPs) found in many pathological processes is offered by positron emission tomography (PET). Hence, appropriate PET radioligands for MMP imaging are required. Here, we describe the syntheses of novel fluorinated MMP inhibitors (MMPIs) based on lead structures of the broad-spectrum inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](benzyl)-amino]-3-methyl-butanamide (CGS 25966) and N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl](3-picolyl)-amino]-3-methyl-butanamide (CGS 27023A). Additionally, tailor-made precursor compounds for radiolabeling with the positron-emitter 18F were synthesized. All prepared hydroxamate target compounds showed high in vitro MMP inhibition potencies for MMP-2, MMP-8, MMP-9, and MMP-13. As a consequence, the promising fluorinated hydroxamic acid derivative 1f was resynthesized in its 18F-labeled version via two different procedures yielding the potential PET radioligand [18F]1f. As expected, the biodistribution behavior of this novel compound and that of the more hydrophilic variant [18F]1j, also developed by our group, indicates that there was no tissue specific accumulation in wild-type (WT) mice.

Analysis of the Growth Dynamics of Angiogenesis-Dependent and -Independent Experimental Glioblastomas by Multimodal Small-Animal PET and MRI

“…The study of this model showed that clinically relevant imaging parameters may miss diffusely infiltrative glioblastoma in the absence of vascular remodeling, thus necessitating the development of improved imaging protocols for diffusely infiltrating tumor cells (e.g., the use of markers for activated matrix metalloproteinases (40), the use of 18 F-3,4-dihydroxyphenylalanine (38,39), or the use of higher dose of 18 F-FLT (30)). As has been detailed by Dhermain et al (9), MRI is the imaging method of choice for patients with gliomas, for whom additional PET (in conjunction with MRI) may reveal important complementary information with regard to detection of hot spots in low-grade lesions; planning of biopsy, surgery, and radiation; and detection of recurrent tumors (9).…”

Radiolabeled Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitors: (Radio)Syntheses and in Vitro and First in Vivo Evaluation

“…25 Analog to compound 2a and 2b the second aromatic ring of compound 3 was The benzylamines used for the synthesis of the MMP-13 inhibitors are represented in Scheme 1. Starting from commercially available 4-hydroxybenzylamine different psubstituted benzylamines were prepared by protection of the amine, substitution reaction with 2-fluoroethyl 4-methylbenzenesulfonate, 26 ethane-1,2-diyl bis(4-methylbenzenesulfonate), 2-7 azidoethyl 4-methylbenzenesulfonate 27 or 3-bromoprop-1-yne and deprotection of the amine with 4 HCl in dioxane. The alkyne substituted BOC-protected amide 6e was subjected to a copper(I) catalyzed click reaction with 1-azido-2-fluoroethane.…”

“…1-azido-2-fluoroethane, 32 and 2-fluoroethyl 4-methylbenzenesulfonate 33 were synthesized following literature procedures. All animal experiments were approved by the North RhineWestphalia Agency for Nature, Environment, and Consumer Protection (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen-LANUV).…”

Molecular targets in aortic aneurysm for establishing novel management paradigms

“…Compared with substrates, inhibitors interact with MMPs in a 1:1 manner and have no signal magnification. Research groups established two nonpeptidic MMP inhibitor-based probes (hydroxamates and barbiturates) to evaluate MMP activity and obtain an ideal outcome (90)(91)(92). By using this approach, MMP inhibitors can be used for imaging targets.…”