Pyridylbenzamidines: versatile ligands for palladium(II)

Recently, we have demonstrated that in copolymerization reactions palladium complexes with nonsymmetric\uf020\uf061-diimines generate more productive catalysts than those having the corresponding symmetric counterparts, highlighting the positive effect of an unbalance in the steric and electronic properties of the N-donor atoms.1 With the aim to verify the more general validity of this principle, we have now studied bidentate N-donor ligands belonging to the family of pyridylbenzamidines (Figure). While the two molecules with R1 = H were reported in literature,2 the N-methyl substituted derivative is new. The NMR characterization of the molecules pointed out the presence of dynamic phenomena in solution, due to the interconversion of several isomers, including tautomers. The coordination chemistry to Pd(II) was studied on [Pd(cod)(CH3)Cl] and [Pd(cod)(CH3)(CH3CN)][PF6]: depending on the precursor and on the ligand, different coordination compounds were obtained, indicating that these molecules can act both as mono- and bidentate ligands. None of the isolated complexes generated active catalysts either for ethylene homopolymerization or for ethylene/methyl acrylate copolymerization. The deactivation pathway was unraveled

Nonsymmetric alpha-diimines in Pd-catalyzed ehtene/polar monomer copolymerization

One of the major unsolved problems in polymer chemistry is represented by the synthesis of functionalized polyolefines, that are currently produced through radical processes, a technology that suffers from high energy consumption, low cost efficiency and poor control over the macromolecule structure.1 The direct, controlled, homogeneously catalyzed copolymerization of ethylene with polar vinyl monomers represents a sustainable technology to overcome these limits. The main catalytic systems reported in the literature are based on Pd(II) compounds with either \uf061-diimines or phosphino-sulfonate ligands.2 Their productivity is thus far low from the values required for an industrial application, and better performing catalysts are strongly needed. With this aim we are studying Pd(II) complexes with new nonsymmetric \uf061-diimines (Ar,Ar'-BIAN) featured by an acenaphthene skeleton and one aryl ring substituted in meta positions with electron-withdrawing groups, while the other ring bears electron-releasing substituents on the ortho positions (Figure up). The related monocationic complexes, [Pd(CH3)(Ar,Ar'-BIAN)(L)][PF6], that include both acetonitrile and dimethyl sulfoxide derivatives, have been applied as precatalysts in the ethylene/methyl acrylate copolymerization under mild conditions of temperature and pressure showing a remarkably different catalytic behaviour depending on the nature of the L ligand (Figure below).3 While the catalyst originated from the acetonitrile precursor was found to be less active than the dmso counterpart and to deactivate within 16 h of reaction, that obtained from the dmso derivative was still active after 48 h achieving a productivity of 350 g P/g Pd. The catalysts with the nonsymmetric Ar,Ar'-BIAN showed a productivity twice as high as that of the catalysts with the corresponding symmetric ligands together with a higher incorporation of the polar monomer into the catalytic product. The latter is a mixture of ethylene oligomers and ethylene/methyl acrylate cooligomers, having the polar monomer at the end of the branches. Detailed investigation on the studied catalytic system will be presented. 1A. Nakamura, S. Ito and K. Nozaki, Chem. Rev., 2009, 109, 5215. 2 a) L.K. Johnson, S. Mecking and M. Brookhart, J. Am. Chem. Soc., 1996, 118, 267; b) E. Drent, R. van Dijk, R. van Ginkel B. van Oort and R.I. Pugh, Chem. Commun., 2002, 744. 3A. Meduri, T. Montini, F. Ragaini, P. Fornasiero, E. Zangrando and B. Milani, ChemCatChem published on the web, DOI: 10.1002/cctc.201200520

Proof-of-Concept Study of the NOTI Chelating Platform: Preclinical Evaluation of ⁶⁴Cu-Labeled Mono- and Trimeric c(RGDfK) Conjugates.

We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three five-membered azaheterocyclic arms for the preparation of <sup>68</sup> Ga- and <sup>64</sup> Cu-based radiopharmaceuticals. Based on this platform, the chelator scaffold NOTI-TVA with three additional carboxylic acid groups for bioconjugation was synthesized and characterized. The primary aims of this proof-of-concept study were (1) to evaluate if trimeric radiotracers on the basis of the NOTI-TVA 6 scaffold can be developed, (2) to determine if the additional substituents for bioconjugation at the non-coordinating NH atoms of the imidazole residues of the building block NOTI influence the metal binding properties, and (3) what influence multiple targeting vectors have on the biological performance of the radiotracer. The cyclic RGDfK peptide that specifically binds to the α <sub>v</sub> ß <sub>3</sub> integrin receptor was selected as the biological model system. Two different synthetic routes for the preparation of NOTI-TVA 6 were explored. Three c(RGDfK) peptide residues were conjugated to the NOTI-TVA 6 building block by standard peptide chemistry providing the trimeric bioconjugate NOTI-TVA-c(RGDfK) <sub>3</sub> 9. Labeling of 9 with [ <sup>64</sup> Cu]CuCl <sub>2</sub> was performed manually at pH 8.2 at ambient temperature. Binding affinities of Cu-8, the Cu <sup>2+</sup> complex of the previously described monomer NODIA-Me-c(RGDfK) 8, and the trimer Cu-9 to integrin α <sub>v</sub> ß <sub>3</sub> were determined in competitive cell binding experiments in the U-87MG cell line. The pharmacokinetics of both <sup>64</sup> Cu-labeled conjugates [ <sup>64</sup> Cu]Cu-8 and [ <sup>64</sup> Cu]Cu-9 were determined by small-animal PET imaging and ex vivo biodistribution studies in mice bearing U-87MG xenografts. Depending on the synthetic route, NOTI-TVA 6 was obtained with an overall yield up to 58 %. The bioconjugate 9 was prepared in 41 % yield. Both conjugates [ <sup>64</sup> Cu]Cu-8 and [ <sup>64</sup> Cu]Cu-9 were radiolabeled quantitatively at ambient temperature in high molar activities of A <sub>m</sub> ~ 20 MBq nmol <sup>-1</sup> in less than 5 min. Competitive inhibitory constants IC <sub>50</sub> of c(RDGfK) 7, Cu-8, and Cu-9 were determined to be 159.5 ± 1.3 nM, 256.1 ± 2.1 nM, and 99.5 ± 1.1 nM, respectively. In small-animal experiments, both radiotracers specifically delineated α <sub>v</sub> ß <sub>3</sub> integrin-positive U-87MG tumors with low uptake in non-target organs and rapid blood clearance. The trimer [ <sup>64</sup> Cu]Cu-9 showed a ~ 2.5-fold higher tumor uptake compared with the monomer [ <sup>64</sup> Cu]Cu-8. Functionalization of NOTI at the non-coordinating NH atoms of the imidazole residues for bioconjugation was straightforward and allowed the preparation of a homotrimeric RGD conjugate. After optimization of the synthesis, required building blocks to make NOTI-TVA 6 are now available on multi-gram scale. Modifications at the imidazole groups had no measurable impact on metal binding properties in vitro and in vivo suggesting that the NOTI scaffold is a promising candidate for the development of <sup>64</sup> Cu-labeled multimeric/multifunctional radiotracers

89Zr-PSMA-617 PET/CT May Reveal Local Recurrence of Prostate Cancer Unidentified by 68Ga-PSMA-11 PET/CT

ABSTRACT: For localization of biochemical recurrence of prostate cancer, 68Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89Zr-PSMA-617 PET/CT revealed a small local recurrence in the prostate bed, facilitating consecutive local therapy. This interesting image points to the potential of PET/CT with 89Zr-labeled PSMA ligands, for example, 89Zr-PSMA-617, for identifying the source of biochemical recurrence despite otherwise negative imaging including conventional PSMA PET/CT

Palladium complexes with simple iminopyridines as catalysts for polyketone synthesis

Four iminopyridines (N-N') differing in the nature of the substituents on the iminic carbon and on the ortho positions of the aryl ring (H or CH3) on the iminic nitrogen were used for the synthesis of neutral and monocationic palladium(ii) complexes of general formulae [Pd(CH3)Cl(N-N')] and [Pd(CH3)(NCCH3)(N-N')][PF6]. The detailed NMR characterization in solution highlighted that: (i) for both series of complexes, the Pd-CH3 signal is progressively shifted to a lower frequency on increasing the number of methyl groups on the ligand skeleton; (ii) for the neutral derivatives, the chemical shift of the (15)N NMR signals, determined through (1)H,(15)N-HMBC spectra, is significantly affected by the coordination to palladium; (iii) the coordination induced shift (CIS) of the nitrogen atom trans to the CH3 ligand is smaller than the other. The structure in the solid state for the neutral derivatives with all the four ligands was solved, pointing out that: (iv) the Pd-C bond distance increases with the basicity of the nitrogen-donor ligand; (v) the Pd-N bond distance correlates well with the CIS value. The combining of the solution and solid state structural features allows stating that: (vi) the Pd-CH3 singlet is a good probe for the electron donor capability of the ligand; (vii) the CIS value might be used as a probe for the strength of the Pd-N bond. All monocationic complexes generated active catalysts for the CO/vinyl arene copolymerization, leading to prevailingly syndiotactic polyketones. The catalyst performances, both in terms of catalyst productivity and polymer molecular weight, correlate well with the precatalyst structural features

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617.

In recent years, radiolabeled tracers targeting prostate-specific membrane antigen (PSMA) have had a tremendous impact on prostate cancer management. Here, we report on the formation of radioactive impurities formed during the clinical production of <sup>177</sup> Lu-labeled PSMA-617. We provide compelling evidence that these impurities are the result of a spontaneous, thermally mediated condensation reaction of the Glu-CO-Lys moiety resulting in the formation of three different five-membered ring systems. Density functional theory (DFT) calculations show that the condensation and cyclization of the Glu-CO-Lys moiety is thermodynamically spontaneous. In cell experiments, no affinity of these cyclized compounds toward PSMA was observed. HPLC analyses of urine samples from patient studies showed rapid renal excretion of these radioactive cyclized species. Radiolabeling conditions were identified that significantly reduced the formation of cyclized side products yielding <sup>177</sup> Lu-labeled PSMA-617 in high radiochemical yield and purity in concordance with current good manufacturing practice (cGMP) requirements