Targeted alpha‐therapy (TAT) has great potential for treating a broad range of late‐stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium‐225 (225Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named ‘crown’, which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized 225Ac‐crown‐αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of 225Ac‐crown‐αMSH showed favorable tumor‐to‐background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of 225Ac‐crown‐αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.

A series of 15 water-soluble titanocene dichloride derivatives containing alkylammonium groups pendant to one (monocationic complexes) or both (dicationic complexes) cyclopentadienyl rings has been synthesized and characterized. The in vitro cytotoxicities of this small library of potential anticancer drugs have been assessed against human lung cancer (H209, A549, H209/CP) and ovarian cancer (A2780, A2780/CP) cell lines, and the results are compared with the cytotoxicities of both cisplatin (cis-PtCl 2 (NH 3 ) 2 ) and a clinical formulation of titanocene dichloride that is commonly used against cisplatin-resistant tumors. While none of the compounds exhibit potency greater than that of cisplatin, several are clearly superior to the clinical formulation. In particular dicationic complexes generally exhibit greater potency than do the corresponding monocationic analogues, and derivatives containing protonated piperidinyl rings exhibit greater potency than do compounds containing protonated 2-aminoethyl or 3-aminopropyl groups. Eight of the compounds, representing a wide range of potencies, were characterized crystallographically but no correlations between effectiveness and structures were obvious.

No abstract

Microwave heating was used to prepare eta5-rhenium carborane complexes in aqueous reaction media. For carboranes bearing sterically demanding substituents, isomerization of the cage from 3,1,2 to 2,1,8 derivatives occurred concomitantly with complexation. Microwave heating was equally effective at the tracer level using technetium-99m, affording access to a new class of synthons for designing novel molecular imaging agents.

Recent clinical results have demonstrated remarkable treatment responses of late-stage cancer patients when treated with alpha-emitting radionuclides such as actinium-225 ( 225 Ac). The resulting intense global effort to produce greater quantities of 225 Ac has triggered a number of emerging technologies to produce this rare, yet important, radionuclide. Accelerator-based methods for increasing global 225 Ac production capacity have focused on the high energy (>100 MeV) proton irradiation of thorium, despite the coproduction of the undesirable 227 Ac byproduct at 0.1−0.3% of the 225Ac activity. We at TRIUMF have developed a process for the production of a 225 Ra/ 225 Ac generator from irradiated thorium that results in an 225 Ac product with reduced 227 Ac content. 225 Ac was separated from irradiated thorium and coproduced radioactive spallation and fission products using a thorium peroxide precipitation method followed by cation exchange and extraction chromatography. Stable and radioactive tracer studies demonstrated the ability of this method to separate Ac from most other elements, providing a directly produced Ac product with measured 227 Ac content of (0.15 ± 0.04)%. A second, indirectly produced Ac product with 227 Ac content of <7.5 × 10 −5 % is obtained by repeating the final extraction chromatography step with the 225 Racontaining fraction. The 225 Ra-derived 225 Ac showed similar or improved quality compared to the initial, directly produced 225 Ac product in terms of chemical purity and radiolabeling capability, the latter of which was comparable with other 225 Ac sources reported in the literature.

For over thirty years, instant labeling kits which involve no purification steps have been the only method used to prepare (99m)Tc radiopharmaceuticals for clinical studies. To address the limitations imposed by instant kits, which is hindering the development of molecularly targeted Tc- and Re-based imaging and therapy agents, a new strategy for the rapid multistep synthesis and purification of organometallic technetium-based molecular probes and corresponding rhenium-based therapeutic analogues was developed. Beginning with MO4(-) (M = (99m)Tc, (186/188)Re), the carbonyl precursor [M(CO)3(H2O)3](+) was synthesized in 3 min in quantitative yield in a microwave reactor. A dipicolyl ligand was added and the chelate complex was formed in high yield in 2 min using microwave heating at 150 degrees C. This was followed by a new purification strategy to remove unlabeled ligand which entailed using a copper resin/C18 solid phase extraction protocol giving the desired product in greater than 78% decay corrected yield (dcy). Conversion to the corresponding succinimidyl active ester was achieved following a 5 min microwave irradiation at 120 degrees C and C18 solid phase extraction purification in 60% dcy. A series of amides were prepared subsequently by microwave heating at 120 degrees C for 5 min producing the desired targets in greater than 86% dcy. The reported method represents a move away from traditional instant kits toward more versatile platform synthesis and purification technologies that are better suited for producing modern molecular imaging and therapy agents.

A series of mono and diaryl rhenium(I)-carborane derivatives were prepared using microwave heating and screened for their affinity for two isoforms of the estrogen receptor (ER). The rhenacarborane derivative [(RR'C 2B9H9)Re(CO)3](-) (R = p-PhOH, R' = H), which was generated by taking advantage of a recently discovered cage isomerization process, and the neutral nitrosated analogue [(RR'C2B9H9)Re(CO)2(NO)] (R = p-PhOH, R' = H) showed the highest affinities of the compounds screened. As a result, the (99m)Tc analogue of one of the leads was produced in high yield (84%) and specific activity in a manner that is suitable for routine production in support of future preclinical and molecular imaging studies.

Dediated to Bdau Jam6 on the occasion of his 70tb birthday. AbstractHighly hindered magnesium and metal-free green 1,2,3,4,8,9,10,1 l,l5,l6,l7,l 8,22,23,24,25'hexadecaneop€ntoxyphthalocyanine and t,Z,:,1,A,S,f0,tt,15,16,11,18,22,23,24,25-hexadeca(cyclohexylmethylor.y)phthalocyanine were prepared via magnesium l-octanolate and 3,4,5,6+etraneopentoxyphthalonitrile or 33,5,6-tetra(cyclohexylmethyloxy) The inertness ofPcs is well known [3], but their classical use as dyes [3] is now overshadowed by other applications taking advantage of the inlense absorption of the Q-band' normally between 670 and 730 nrn. Highly red-shifted anatogs of Pcs,-having additional benzo groups attached to the Pc benzo groups (the naphthalocyanines and even anthracenocyanines [4] are usually difficult to prepare, highly insoluble, and prone to decomposition [5]. It has long been known that Pcs containing electron-donating substituents at the 1,4,8,! 1,15,18,22,25 substituents) show some red-shifts of the Pc chromophore, but that only minor shifts occur due to substituents placed at the 2, 3,9,10,16,17,23,24 positions (the peripheral substituents) [6][7][8]. On the other hand some hexadecaalkoxysubstituted Pc nickel cornpounds exhibited enhanced red shifts, showing a Q-band shifted to as long a wavelength as 745 nm [9]. It appears that the substituents at the peripheral positions buttress the substituents at the non-peripheral posilions effeotively making the non-peripheral substituents bulkier.In this spirit, in previous res€arch in the Lezno Further reduction at -1.6V versus Fc*/Fc (Fig. 3) yiolds a spectrum consistent with expectation for a Pc(3-) radical anion t2l-241 Curiously, the absorption bands in the 700 nm region for this species are closely similar to those of the Mnl! precursor. There is growth ol a weak band near 900 nm. The electrochemical data shown in Fig. 4 Spectroelectrochem.istry, discussed below, shows that peak I (Fig. 4) (Fig. 4! ihe nature of the second species was not further studied.Oxidation at peak VI yielded a spectrum (Fig. 9) typical P2-24,26) of tn-e radical cation phthalocyanino(l-) species, and hence the formation of [NeoPdl-)Mnlv absorption between 500 and 600 nm to which we return in Section 3.5. The Mn(II)Pc(3-) spectra are also targely similar with three peaks in the visible region and a weak absorption around 900 nrn. This provides a means to change the counter axial anion by simply changing the acid used. The counter-ion does, as expected, have a small but noticeable eflect on the spectrum. Table I Variation of axial counter-ion