Structure determination of two metal-organic complexes from high-resolution synchrotron powder diffraction data.

The crystal structures of [1,2-bis(2,6-diisopropylphenylimino)acenaphthene-N,N']carbonylchlororhodium(I) (1) and [N,N'-ethylene-bis(3-methylsalicylideneiminato)-O,N,N',O'](tetrahydrofurfuryl)-cobalt(II) (2) have been determined from high-resolution synchrotron X-ray powder diffraction data. Compound 1 is the first neutral Rh complex, in contrast with findings in the literature, containing a bidentate nitrogen ligand, and compound 2 is the first three-dimensional structure of a (five-coordinated) tetrahydrofurfurylcobalt(III) complex. Grid-search and Rietveld refinement have been used to determine and refine the structures, respectively. Crystals of 1 are orthorhombic, space group Pbca, Z = 8, with cell parameters a = 21.729 (2), b = 27.376 (3), c = 11.580 (1) A. Crystals of 2 are monoclinic, space group P2(1)/n, Z = 4, a = 16.6701 (6), b = 9.4170 (4), c = 13.7088 (7) A and beta = 96.520 (3) degrees. Chemical diagrams for the two compounds are given. Soft restraints were applied during Rietveld refinement; for 1 converging to R(p) = 8.4%, R(w) = 11.0%, GoF = 2.3, and for 2 converging to R(p) = 8.5%, R(w) = 11.4%, GoF = 7.6.

Structure of beta-trimyristin and beta-tristearin from high-resolution X-ray powder diffraction data.

The crystal structures of beta-1,2,3-tritetradecanoylglycerol (beta-trimyristin or beta-MMM) and beta-1,2,3-trioctadecanoylglycerol (beta-tristearin or beta-SSS) have been determined from high-resolution synchrotron X-ray powder diffraction data. Grid search and Rietveld refinement have been used to determine and refine the structure, respectively. Both substances crystallize in space group P1; with Z = 2. The unit-cell parameters for beta-MMM are a = 12.0626 (6), b = 41.714 (1), c = 5.4588 (3) A, alpha = 73.388 (4), beta = 100.408 (5) and gamma = 118.274 (4) degrees. For beta-SSS the unit-cell parameters are a = 12.0053 (7), b = 51.902 (2), c = 5.4450 (3) A, alpha = 73.752 (5), beta = 100.256 (6) and gamma = 117.691 (5) degrees. Soft-distance restraints have been applied to the molecules during refinement. For beta-MMM the final R(p) value obtained is 0.053 and for beta-SSS the final R(p) value is 0.041.

Structure of CnCn+2Cn-type (n = even) beta'-triacylglycerols.

The crystal structures of the beta' phase of CLC (1, 3-didecanoyl-2-dodecanoylglycerol) and MPM (1, 3-ditetradecanoyl-2-hexadecanoylglycerol) have been determined from single-crystal X-ray diffraction and high-resolution X-ray powder diffraction data, respectively. Both these crystals are orthorhombic with space group Iba2 and Z = 8. The unit-cell parameters of beta'-CLC are a = 57.368 (6), b = 22.783 (2) and c = 5.6945 (6) A and the final R value is 0.175. The unit-cell parameters of beta'-MPM are a = 76.21 (4), b = 22.63 (1) and c = 5.673 (2) A and the final R(p) value is 0.057. Both the beta'-CLC and beta'-MPM molecules are crystallized in a chair conformation, having a bend at the glycerol moiety. The zigzag planes of the acyl chains are orthogonally packed, as is typical for a beta' phase. Furthermore, unit-cell parameters of some other members of the C(n)C(n+2)C(n)-type triacylglycerol series have been refined on their high-resolution X-ray powder diffraction pattern. Finally, the crystal structures are compared with the currently known structures and models of triacylglycerols.

Structure of mono-acid even-numbered beta-triacylglycerols.

The crystal structure of the beta polymorph of tripalmitin (1,2,3-trihexadecanoylglycerol, beta-PPP) has been determined by single-crystal X-ray diffraction. The molecules crystallize in space group P1; in an asymmetric tuning-fork conformation. This structure and the already-known crystal structures of beta-tricaprin (beta-CCC) and beta-trilaurin (beta-LLL) could be matched in an overlap model. Apart from a difference in chain length, the three structures are almost identical. The overlap model can be used to predict the crystal structure of the other members of the C(n)C(n)C(n)-type (n = even) TAG series reasonably accurately. This is demonstrated by predicting the crystal structure for beta-trimyristin (beta-MMM) and successively comparing the experimental and calculated X-ray powder diagrams.

Potential radiopharmaceuticals for the detection of ocular melanoma. Part III. A study with 14C and 11C labelled tyrosine and dihydroxyphenylalanine.

In order to investigate the possibility of using [1-11C] labelled 3,4-dihydroxyphenylalanine (DOPA) and tyrosine as radiopharmaceuticals for the detection of eye melanoma, the biodistributions of the same 1- and 3-14C-labelled compounds were investigated in Syrian golden hamsters with Greene melanoma. The results of these investigations were compared with positron emission tomography (PET) images of 11C labelled DOPA and tyrosine. The synthesis of these 11C labelled compounds procures of DL mixture, from which D and L forms can be separated. One h after intravenous injection, both 14C labelled DL-, L- and D-DOPA showed a high uptake in tumour tissue, that of DL- and D-DOPA being the highest. These high uptakes, together with relatively low uptake in bone, skin and eye resulted in high tumour/non tumour ratio (for DL-DOPA 5.9, 4.5 and 6.6 respectively). Extraction of the tumour tissue with trichloroacetic acid showed that L-DOPA was mainly incorporated into melanin, whereas D-DOPA was not. Also, the uptake 1 h after intravenous injection of 1-14C-L- and DL-tyrosine into the tumour were high, but L- and DL- were less different; tumour/non tumour ratios were favorable. PET images of the tumour obtained 40-80 min after injection of the [1-11C] labelled DOPA and tyrosine confirmed that melanoma detection was promising and that D-DOPA produced a better melanoma image than L-DOPA.

Radio-iodine-labelled 5-iodo-2-thiouracil: a potential radiopharmaceutical for establishing the viability of ocular melanoma after radiation therapy.

Radio-iodine-labelled thiouracil has been evaluated as a radiopharmaceutical for establishing the viability of ocular melanoma after radiation treatment. The uptake of 125I-5-iodo-2-thiouracil (125I-ITU) was studied in X-ray irradiated and non-irradiated melanotic melanomas implanted in Syrian golden hamsters. Uptake of 125I-ITU in melanomas 4 days after irradiation with 40 Gy X-ray was 25% of the value found in non-irradiated controls, 12 days after such treatment it was 10% of that value. Twenty-one days after radiation treatment the melanomas showed regrowth and uptake of 125I-ITU was about equal to that in non-treated controls. Uptake of 125I-ITU in melanomas after 10 Gy X-ray irradiation was higher and uptake in tumours after 20 Gy was only slightly lower than the uptake by non-irradiated melanomas. The results indicate that the iodine labelled-thiouracil uptake test may be useful as an additional diagnostic issue for assessing the viability of ocular melanoma after radiation therapy.

Potential radiopharmaceuticals for the detection of ocular melanoma. Part II. Iodoquinoline derivatives and 67Ga-citrate.

The uptake and distribution of several 4-(substituted amino)-iodoquinolines, 131I-labelled, and of 67Ga-citrate were investigated in Syrian golden hamsters with Greene melanomas. Because of its uptake in the melanoma (tumour/eye ratio 8.9), 4-(dimethylamino-ethylamino)-7-iodoquinoline (NM113) was selected for further investigations as a possible radiopharmaceutical for ocular scintigraphy when labelled with 123I. High uptake of NM113 turned out to be incidental and could not be favourably influenced by several pharmacological pretreatments. Affinity for melanin, as shown in in vitro experiments, unfavourably influences NM113 tumour-to-eye ratios. In comparison with 67Ga-citrate, the latter, with a high tumour-to-eye ratio (44.8 after 24 h) is more promising in patient studies in which NM113 123I was not.

Scintimetric detection of choroidal malignant melanoma with [123I]-5-iodo-2-thiouracil.

[123I]-5-iodo-2-thiouracil (123I-ITU) was evaluated as a radiopharmaceutical for tumor detection in 10 patients with proven choroidal melanoma. Uptake of 123I-ITU was measured with a specially designed single eye probe collimator, 24 h after administration of 123I-ITU. Increased uptake in the tumor-bearing eye as compared to the fellow nontumor bearing eye was found in 7 out of 10 cases when the probe was located 3.5 cm in front of the eye (p less than 0.01). By using a double pinhole collimator tests were positive in 3 out of 10 123I-ITU studies only. Tests with 123I-ITU were compared with 67Ga tests in the same patients. The 67Ga tests with the single eye probe collimator were positive in 6 out 10 cases when the probe was located 6 cm in front of the eye. With the double pinhole collimator tests were positive in 7 out of 10 67Ga studies. It is concluded that 123I-labeled thiouracil is at least as useful as a radiopharmaceutical for ocular melanoma diagnosis as 67Ga-citrate, provided measurements are performed with a single eye probe.

Bone scintigraphy in oncology: an update with emphasis on efficacy and cost-effectiveness.

Bone scintigraphy has been helpful to oncologists in the initial evaluation and diagnostic follow-up of patients with primary and secondary neoplasms. This review discusses this way of bone imaging with respect to the choice of the bone seeking radiopharmaceutical and puts emphasis on its diagnostic yield and cost-effectiveness in various malignant diseases.

Uptake of 123I-5-iodo-2-thiouracil, a possible radiopharmaceutical for noninvasive detection of ocular melanoma, in melanotic and amelanotic melanomas in hamsters.

The uptake of 123I-5-iodo-2-thiouracil in melanotic and amelanotic melanoma implanted in Syrian golden hamsters was studied. A selective accumulation was found in the tumours. Uptake of 123ITU in melanotic melanomas was 4 to 5 times the uptake in amelanotic ones. For both tumours high ratios of tumours versus non-tumour were found. The high accumulation of 123ITU in both kinds of tumours and the high tumour versus non-tumour ratios suggest that 123ITU may be a promising radiopharmaceutical for the detection of ocular melanoma.

Binding of [3H]flunitrazepam and [3H]spiperone to melanoma cell membrane preparations.

Binding of [3H]flunitrazepam and [3H]spiperone to membrane preparations isolated by high speed centrifugation of hamster, rabbit and human melanoma cell homogenates was analyzed. All melanoma cell types expressed a high density of specific binding sites for [3H]flunitrazepam (3-4 pmol/mg protein) with a high affinity (Kd about 30 nM). This binding was independent of melanin content of cells and could be classified, based on competition experiments, as a Ro 5-4864-like binding type. Specific [3H]spiperone binding to these cell lines clearly revealed at least two types of binding sites: a low affinity, high capacity type of binding site (Kd greater than 100 nM, Bmax about 50 pmol/mg protein) and a high affinity, low capacity binding site (Kd less than 1 nm, Bmax 30 fmol/mg protein). Binding of spiperone to the low affinity, high capacity site appeared displaceable by NM 113 and dependent on melanin content of the cells and probably represents binding to melanin. Analysis of drug binding to melanoma membrane cell preparations and correlation with drug effects should include the possible involvement of binding to melanin.

Incorporation of [125I]-5-iodo-2-thiouracil in cultured hamster, rabbit, and human melanoma cells.

The incorporation of [2-14C]-2-thiouracil and a series of [125I]-5-iodo-2-thiouracils ([125I]ISUra(s)) into cultured Greene hamster melanoma cells was determined in order to establish their properties as false precursors in the melanin-biosynthetic pathway. The cold trichloroacetic acid-precipitable incorporation of [2-14C]-2-thiouracil as well as [125I]ISUra into melanoma cells after a 24- to 48-hr labeling period proved to be completely tyrosinase dependent (more than 99.5% inhibition could be achieved by 0.5 mM phenylthiourea). [125I]ISUra incorporation was 3-fold higher than was [2-14C]-2-thiouracil incorporation and was enhanced by 1 mM theophylline treatment. [125I]ISUra incorporation into hamster, rabbit, and human melanoma cells showed a linear relationship with cell melanin content. Methylation of the sulfur completely prevented the incorporation, while propylation but not methylation at position 6 resulted in lower incorporation. [125I]ISUra proved to be a marker for melanogenesis and may be useful in studies on the differentiation of cultured melanoma cells.

Potential radiopharmaceuticals for the detection of ocular melanoma. Part I. 5-iodo-2-thiouracil derivatives.

The tissue distribution of a number of 5-[131I]-iodo-2-thiouracil derivatives was measured in Syrian golden hamsters with Greene melanoma. These compounds were rapidly (in less than 1 h) distributed in all tissues, while in most tissues fast elimination (T1/2 1-3 h) was observed. Because of retention of the 131I activity in the tumour, high tumour/non-tumour tissue ratios were found (e.g. tumour/eye 2.3-10, tumour/skin 1.5-3) suggesting that some of these compounds might be used as melanoma delineating agents, when labelled with 123I.