Synthesis and biodistribution of [99mTc]-N-[4-nitro-3-trifluoromethyl-phenyl] cyclopentadienyltricarbonyltechnetium carboxamide, a nonsteroidal antiandrogen flutamide derivative

Abstract

In our efforts to develop a novel class of SPECT imaging agents based on nonsteroidal androgen receptor (AR) antagonists, we have synthesized N-cyclopentadienyltricarbonyltechnetium-N-[4-nitro-3-trifluoromethyl-phenyl] carboxamide (NF(99m)Tc), an analog of the AR antagonist ligand flutamide. NF(99m)Tc was obtained in 82% yield from the reaction of N-[4-nitro-3-trifluoromethyl-phenyl]-ferrocenecarboxamide (NFFe) with fac-[(99m)Tc(H(2)O)(3)(CO)(3)](+) in DMF-water at pH 1 and at 150 °C for 1 h. The corresponding Re analog was also prepared. In vitro assays demonstrated high stability of NF(99m)Tc under physiological conditions, buffer and blood. The tissue biodistribution in mature male Wistar rats showed a significant selective uptake by prostate but this uptake was not blocked by an excess of testosterone acetate. A higher uptake by lung tissues was observed.

PET and SPECT Imaging of Steroid Hormone Receptors

“…However, in vivo evaluation in rats did not show any AR-mediated specifi c binding for any of these compounds (Dallagi et al 2010 ;Dhyani et al 2011 ).…”

Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide

“…Recently the synthesis of rhenium and technetium derivatives of flutamide was reported by Benny et al as a novel class of single photon emission computer tomography (SPECT) imaging agents [23,24]. Our group also reported the synthesis of cyclopentadienyl-M-tricarbonyl derivatives (M ¼ Re or Tc) of flutamide using the novel ferrocenyl derivative of flutamide 1 as the starting material (Chart 2) [25].…”

“…The synthesis of 1 bearing a nitro substituent on the aromatic ring has recently been described [25] and the cyano analogue 2 was prepared following the same procedure, i.e. by treating the acid chloride formed from ferrocene carboxylic acid and oxalyl chloride with 4-cyano-3-trifluoromethyl-aniline in the presence of triethylamine to give N-(4-cyano-3-trifluoro-phenyl)-ferrocenylamide 2 in 48% yield (Scheme 1).…”

“…The synthesis of SARM S-1 was carried out following the literature procedure [14] as well as (R)-10 and (S)-10 [27,29], 1 [25], 6 and 7 [8,26] and hydroxy-flutamide [35].…”

Organometallic Complexes for SPECT Imaging and/or Radionuclide Therapy

“…Published work is based on the use of cysteine, histidine, and Cp ligands functionalized with flutamide, a potent nonsteroidal antiandrogen. These conjugates were labeled with fac -[M(CO) 3 ] + (M = Re, 99m Tc) (e.g., 51 and 52 , Figure ). , The Cp-based complex 52 showed some uptake by the prostate but was not AR mediated. Like the cysteine congener, the flutamide-containing histidine 99m Tc(I) tricarbonyl complex 51 presented a modest in vitro binding to the androgen-positive DU-145 prostate cancer cell line.…”