Development of 177Lu-scFvD2B as a Potential Immunotheranostic Agent for Tumors Overexpressing the Prostate Specific Membrane Antigen

The clinical translation of theranostic 177Lu-radiopharmaceuticals based on inhibitors of the prostate-specific membrane antigen (PSMA) has demonstrated positive clinical responses in patients with advanced prostate cancer (PCa). However, challenges still remain, particularly regarding their pharmacokinetic and dosimetric properties. We developed a potential PSMA-immunotheranostic agent by conjugation of a single-chain variable fragment of the IgGD2B antibody (scFvD2B) to DOTA, to obtain a 177Lu-labelled agent with a better pharmacokinetic profile than those previously reported. The labelled conjugated 177Lu-scFvD2B was obtained in high yield and stability. In vitro, 177Lu-scFvD2B disclosed a higher binding and internalization in LNCaP (PSMA-positive) compared to PC3 (negative control) human PCa cells. In vivo studies in healthy nude mice revealed that 177Lu-scFvD2B present a favorable biokinetic profile, characterized by a rapid clearance from non-target tissues and minimal liver accumulation, but a slow wash-out from kidney. Micro-SPECT/CT imaging of mice bearing pulmonary microtumors evidenced a slow uptake by LNCaP tumors, which steadily rose up to a maximum value of 3.6 SUV at 192 h. This high and prolonged tumor uptake suggests that 177Lu-scFvD2B has great potential in delivering ablative radiation doses to PSMA-expressing tumors, and warrants further studies to evaluate its preclinical therapeutic efficacy

Synthesis and biological evaluation of Technetium(III)-based radiopharmaceuticals

Development of new 99mTc and 186/188Re radiopharmaceuticals still remain an interesting research topic because of their almost ideal nuclear properties. 99mTc is the radioisotope of election for SPECT‐imaging (Eγ=140 keV, t1/2=6.02 h), while 186/188Re are radionuclides with an important therapeutic potential (186Re: Eβ‐=1.07 MeV, Eγ=137 keV, t1/2=90.6 h; 188Re: Eβ‐ =2.12 MeV, Eγ=155 keV, t1/2=17 h). Compounds of both Tc and Re in the 3+ oxidation state are well known, however, the chemistry of Tc(III) and Re(III) applied to Nuclear Medicine is still relatively unexplored. This study reports the synthesis and evaluation of a new class of stable, mixed hexacoordinated [99mTcIII(PS)2(L)] complexes, where PS is a phosphinothiolate, and L is a dithiocarbamate. The asymmetric structure potentially allow a fine tuning of the biological and pharmacokinetical behavior of the final compounds through appropriate chemical modifications of the ligands; derivatizations of L can also be conjugated with a biologically active molecule in order to obtain target‐specific radiolabeled compounds. A series of model complexes where M=Re,99gTc and PS=(diphenylphosphino)ethanethiolate (PS2) or 2‐(diisopropylphosphino)ethanethiolate (PSiso) were firstly prepared and characterized. Then, four analogues 99mTc‐radiolabeled complexes are prepared and biologically evaluated.Lo sviluppo di nuovi radiofarmaci a base di Tecnezio‐99m e Renio 186/188 è ancora un campo attuale di ricerca, viste le caratteristiche ideali che questi radionuclidi presentano per l’imaging Medico Nucleare e per la Radioterapia. Lo stato di ossidazione 3+ rappresenta uno dei più comuni e stabili stati di ossidazione del Renio e del Tecnezio. Tuttavia la chimica del Tc(III) e del Re(III) applicata alla Medicina Nucleare continua ad essere poco esplorata. Ciò è dovuto al fatto che la preparazione di tali complessi è generalmente condotta in solventi non acquosi e di conseguenza difficilmente applicabile alla produzione di radiofarmaci in condizioni idonee alla somministrazione nell’uomo. Gli unici esempi di agenti utilizzati in pratica clinica sono il 99mTc‐Teboroxime (un complesso della classe BATO che era utilizzato per l’imaging cardiaco), e il complesso [99mTc(HIDA)2]‐, tutt’oggi utilizzato per l’imaging della funzionalità epatobiliare (HIDA Scan). Questo studio presenta la sintesi e la caratterizzazione di una nuova classe di composti del tecnezio e del renio allo stato di ossidazione III, aventi formula generale [MIII(PS)2(L)], dove PS = fosfinotiolato e L = ditiocarbammato. E’ stato effettuato dapprima uno studio a livello “macroscopico”, di sintesi e caratterizzazione di complessi con gli isotopi 185/187Re e 99gTc. Quindi, quattro analoghi radiocomplessi a base di 99mTc sono stati preparati e valutati nella loro stabilità e nel comportamento biodistributivo in ratti Sprague‐Dawley sani

Reactivity of the [M(PS)2]+Building Block (M = ReIIIand99mTcIII; PS = Phosphinothiolate) toward Isopropylxanthate and Pyridine-2-thiolate

none4The coordination properties of isopropylxanthate (i-Pr-Tiox) and pyridine-2-thiolate (PyS) toward the [M(PS)(2)](+) moiety (M = Re and Tc-99m; PS = phosphinothiolate) were investigated. Synthesis and full characterization of [Re(PS2)(2)(i-Pr-Tiox)] (Re1), [Re(PSiso)(2)(i-Pr-Tiox)] (Re2), [Re(PS2)(2)(PyS)] (Re3), and [Re(PSiso)(2)(PyS)] (Re4), where PS2 = 2-(diphenylphosphino)ethanethiolate and PSiso = 2-(diisopropylphosphino)ethanethiolate, and the structural X-ray analysis of complex Re3 were carried out. Tc-99m analogues of complexes Re2 ((99m)Tc2) and Re4 ((99m)Tc4) were obtained in high radiochemical yield following a simple one-pot procedure. The chemical identity of the radiolabeled compounds was confirmed by chromatographic comparison with the corresponding rhenium complexes and by dual radio/UV HPLC analysis combined with ESI(+)-MS of 99g/Tc-99m complexes prepared in carrier-added conditions. The two radiolabeled complexes were stable with regard to trans chelation with cysteine, glutathione, and ethylenediaminotetraacetic acid and in rat and human sera. This study highlights the substitution-inert metal-fragment behavior of the [M(PS)(2)](+) framework, which reacts with suitable bidentate coligands to form stable hexacoordinated asymmetrical complexes. This feature makes it a promising platform on which to develop a new class of Re/Tc complexes that are potentially useful in radiopharmaceutical applications.noneNicola Salvarese;Alessandro Dolmella;Fiorenzo Refosco;Cristina BolzatiSalvarese, Nicola; Dolmella, Alessandro; Fiorenzo, Refosco; Cristina, Bolzat

Copper(II) and copper(I) complexes with a bidentate hydrazinic dithiocarbazate: synthesis and crystal structures

In this work, we explored the ability of N-methyl-S-methyl dithiocarbazate ([H2N-N(CH3)C(=S)SCH3]; DTCZ) to form coordination complexes with copper starting from different copper (II, I) sources. Data proved that the type of used salt affects the stoichiometry and structure of the obtained coordination complexes. Copper complexes of general empirical formula [Cu(DTCZ)Cl2] (1), [Cu(DTCZ)2NO3]NO3 (2), [Cu(DTCZ)2(OH2)]SO4 (3), [Cu(DTCZ)2]PF6 (4), [Cu(DTCZ)(PPh3)2]NO3 (5) and [Cu(DTCZ)2]Br (6) were synthesized in high yield and characterized by elemental analysis, UV-Vis and IR spectroscopy. Molecular structures of 1-6 and also of side- products [Cu(DTCZ)2SO4] (3a), [Cu(DTCZ)2](PF6)(OH) (4b) and [CuBr(C3H7NS2)]n (6a) were determined by single crystal X-ray diffraction (XRD). In all cases, DTCZ binds the metal in the neutral form through the hydrazine nitrogen (NH2) and thione sulphur (S) atom set, forming monosubstituted and disubstituted complexes having tetrahedral, square planar, or square pyramidal geometries, depending on the copper source. In addition, two one-dimensional (1D) coordination polymers and water channels have been observed in the crystal states

Improved synthesis on solid phase of dithiocarbamic cRGD-derivative and 99m Tc-radiolabelling

In the field of angiogenesis, small cyclic pentapeptides containing the RGD motif are playing a relevant role for their high affinity and specificity for integrin receptors and for the possibility to act at both therapeutic and diagnostic level by inhibiting pathological angiogenesis and by serving as shuttles to deliver imaging-probe including SPECT/PET radionuclides to specific tissues. In the last decade, several new protocols were reported in literature for the direct synthesis of cyclic RDG either in solution or by SPPS. Here, we have elaborated and tested some alternative approaches using different resins and different protective groups. The introduction of the dithiocarbamate function, useful to complex radio-metals suitable for nuclear medicine applications, has also been considered and achieved