Radiofluorination method

Abstract

The present invention relates to a method of labelling biological molecules with .sup.18F, via attachment to fluorine to a macrocyclic metal complex of a non-radioactive metal, where the metal complex is conjugated to the biological molecule. Also provided are pharmaceutical compositions, kits and methods of in vivo imaging.

Claims

1. An imaging agent which comprises an .sup.18F-labelled compound of Formula I: ##STR00016## where: Y.sup.1 and Y.sup.2 are independently O or NR.sup.1, where R.sup.1 is C.sub.1-3 alkyl or —CH.sub.2—Ar.sup.1, wherein Ar.sup.1 is C.sub.5-12 aryl or C.sub.3-12 heteroaryl; X.sup.1, X.sup.2 and X.sup.3 are independently .sup.19F or .sup.18F, with the proviso that at least one of X.sup.1, X.sup.2 and X.sup.3 is .sup.18F and at least one of the remaining X.sup.1, X.sup.2, and X.sup.3 is .sup.19F; M is Al.sup.3+, Ga.sup.3+, In.sup.3+, Se.sup.3+, Y.sup.3+, Ho.sup.3+, Er.sup.3+, Tm.sup.3+, Yb.sup.3+or Lu.sup.3+; x, y and z are 1; R.sup.2 is R.sup.1 or Q; Q is -L-[BTM], and may be present or absent; when present it is either R.sup.2 or is attached at one of the carbon atoms of the —(CH.sub.2)(CH.sub.2).sub.x—, —(CH.sub.2)(CH.sub.2).sub.y— or —(CH.sub.2)(CH.sub.2).sub.z— groups, where BTM is a biological targeting moiety; wherein L is a synthetic linker group of formula -(A).sub.m- wherein each A is independently —CR.sup.3.sub.2—, —CR.sup.3═CR.sup.3—, —C═C—, —CR.sup.3.sub.2CO.sub.2—, —CO.sub.2CR.sup.3.sub.2—, —NR.sup.3CO—, —CONR.sup.3—, —CR.sup.3═N—O—, —NR.sup.3(C═O) NR.sup.3—, —NR.sup.3(C═S)NR.sup.3—, —SO.sub.2NR.sup.3—, —NR.sup.3SO.sub.2, —CR.sup.3.sub.2OCR.sup.3.sub.2, —CR.sup.3.sub.2SCR.sup.3.sub.2, —CR.sup.3.sub.2NR.sup.3CR.sup.3.sub.2—, a C.sub.4-8 cycloheteroalkylene group, a C.sub.4-8 cycloalkylene group, —Ar.sup.2—, —NR.sup.3—Ar.sup.2—, —O—Ar.sup.2—, —Ar.sup.2—(CO)—, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block, wherein each R.sup.3 is independently chosen from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxyalkyl or C.sub.1-4 hydroxyalkyl; m is an integer of value 1 to 20; and each Ar.sup.2 is independently a C.sub.5-12 arylene group, or a C.sub.3-12 heteroarylene group.

2. The agent of claim 1, where Q is present.

3. The agent of claim 1, which is of Formula IA: ##STR00017##

4. The agent of claim 1, where Y.sup.1═Y.sup.2═NR.sup.1.

5. The agent of claim 1, which is of Formula IB: ##STR00018##

6. A method of preparation of the agent of claim 1, which comprises reaction of a precursor of Formula II at room temperature with a supply of [.sup.18F]-fluoride or [.sup.18F]NaF, and in the presence of [.sup.19F]-fluoride, in a suitable solvent: ##STR00019## where M, Y.sup.1, Y.sup.2, x, y and z are as defined in claim 1; and X.sup.1a, X.sup.2a and X.sup.3a are independently Br or Cl.

7. The method of claim 6, where the precursor is of Formula IIA: ##STR00020##

8. The method of claim 6, where the precursor is of Formula IIB: ##STR00021##

9. The method of claim 6, where X.sup.1a=X.sup.2a=X.sup.3a═Cl.

10. A radiopharmaceutical composition which comprises the agent of claim 1, together with an aqueous biocompatible carrier, wherein the composition is in a form suitable for mammalian administration and has a pH range of 4 to 10.5.

11. A method of preparation of the agent of claim 1, which comprises reaction of a precursor of Formula II at room temperature with a supply of [.sup.18F]-fluoride or [.sup.18F]NaF, and in the presence of [.sup.19F]-fluoride, in a suitable solvent: ##STR00022## where M, Y.sup.1, Y.sup.2, x, y and z are as defined in claim 1; and X.sup.1a, X.sup.2a and X.sup.3a are independently Br or Cl; using an automated synthesizer apparatus.

12. The method of claim 11, where the automated synthesizer apparatus comprises a cassette which comprises the non-radioactive reagents necessary to carry out the method.

13. The method of claim 11, wherein the precursor is provided in sterile, lyophilized form.

14. A method of imaging the human or animal body which comprises generating an image of at least a part of said body to which the imaging agent of claim 1 has distributed using PET, wherein said agent has been previously administered to said body.

15. A method of imaging the human or animal body which comprises generating an image of at least a part of said body to which the composition of claim 10 has distributed using PET, wherein said composition has been previously administered to said body.

16. An imaging agent which comprises an .sup.18F-labelled compound of Formula IA: ##STR00023## where: Y.sup.1 and Y.sup.2 are NR.sup.1, where R.sup.1 is C.sub.1-3 alkyl or —CH.sub.2—Ar.sup.1, wherein Ar.sup.1 is C.sub.5-12 aryl or C.sub.3-12 heteroaryl; X.sup.1, X.sup.2 and X.sup.3 are independently .sup.19F or .sup.18F, with the proviso that at least one of X.sup.1, X.sup.2 and X.sup.3 is .sup.18F and at least one of the remaining X.sup.1, X.sup.2, and X.sup.3 is .sup.19F; M is Ga.sup.3+ or In.sup.3+; x, y and z are 1; Q is -L-[BTM], where BTM is a biological targeting moiety; wherein L is a synthetic linker group of formula -(A).sub.m- wherein each A is independently —CR.sup.3.sub.2—, —CR.sup.3=CR.sup.3—, —C═C—, —CR.sup.3.sub.2CO.sub.2—, —CO.sub.2CR.sup.3.sub.2—, —NR.sup.3CO—, —CONR.sup.3—, —CR.sup.3═N—O—, —NR.sup.3(C═O) NR.sup.3—, —NR.sup.3(C═S)NR.sup.3—, —SO.sub.2NR.sup.3—, —NR.sup.3SO.sub.2, —CR.sup.3.sub.2OCR.sup.3.sub.2, —CR.sup.3.sub.2SCR.sup.3.sub.2, —CR.sup.3.sub.2NR.sup.3CR.sup.3.sub.2—, a C.sub.4-8 cycloheteroalkylene group, a C.sub.4-8 cycloalkylene group, —Ar.sup.2—, —NR.sup.3—Ar.sup.2—, —O—Ar.sup.2—, —Ar.sup.2—(CO)—, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block; wherein each R.sup.3 is independently chosen from H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.1-4 alkoxyalkyl or C.sub.1-4 hydroxyalkyl; m is an integer of value 1 to 20; and each Ar.sup.2 is independently a C.sub.5-12 arylene group, or a C.sub.3-12 heteroarylene group.

17. The agent of claim 16, which is of Formula IB: ##STR00024##

18. A radiopharmaceutical composition which comprises the agent of claim 16, together with an aqueous biocompatible carrier, wherein the composition is in a form suitable for mammalian administration and has a pH range of 4 to 10.5.

19. The agent of claim 1, where M is Ga.sup.3+or In.sup.3+.

Description

DESCRIPTION OF THE FIGURES

(1) FIGS. 1 to 3 show the X-ray crystal structures of metal complexes of the invention.

EXAMPLE 1

Synthesis of [AlCl.SUB.3.(Me-tacn)]

(2) AlCl.sub.3 (0.067 g, 0.50 mmol) was added to a solution of Me.sub.3-tacn (0.086 g, 0.50 mmol) in CH.sub.3CN (5 mL) at room temperature with stirring leading to rapid formation of a precipitate. After 30 mins. the solvent was removed by filtration. The white precipitate was washed with small amount of CH.sub.2Cl.sub.2 solvent and dried in vacuo. Yield: 0.11 g, 72%. Colorless crystals were obtained by cooling the CH.sub.3CN solution in the fridge for several days. The crystals were washed with CH.sub.2Cl.sub.2.

(3) Anal. Calc. for C.sub.9H.sub.21AlCl.sub.3N.sub.3. 0.2 CH.sub.2Cl.sub.2: C, 34.4; H, 6.7; N, 13.1. Found: C, 34.2; H, 7.2; N, 13.9.

(4) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 3.23 (m, [6H], CH.sub.2), 2.86 (s, [9H], CH.sub.3), 2.67 (m, [6H], CH.sub.2).

(5) IR (Nujol, v/cm.sup.−1): 389, 375 (Al—Cl).

(6) An X-ray crystal structure was obtained, see FIG. 1.

EXAMPLE 2

Synthesis of [AlBr.SUB.3.(Me.SUB.3.-tacn)]

(7) Al Br.sub.3 (0.133 g, 0.50 mmol) was added to a solution of Me.sub.3-tacn (0.086 g, 0.50 mmol) in CH.sub.2Cl.sub.2 (5 mL) at room temperature with stirring which leads a formation of precipitate. After 30 mins. the solvent was removed by filtration. The white precipitate was washed with small amount of CH.sub.2Cl.sub.2 solvent and dried in vacuo. Yield: 0.16 g, 74%.

(8) Anal. Calc. for C.sub.9H.sub.21Al Br.sub.3N.sub.3: C, 24.7; H, 4.8; N, 9.6. Found: C, 24.6; H, 5.3; N, 8.9.

(9) .sup.1H NMR (CD.sub.2Cl.sub.2, 297 K): δ 3.43 (m, [6H], CH.sub.2), 2.98 (m, [9H], CH.sub.3), 2.73 (m, [6H], CH.sub.2).

(10) IR (Nujol, v/cm.sup.−1): 324 (Al—Br).

EXAMPLE 3

Synthesis of [AlF.SUB.3.(Me.SUB.3.-tacn)].Math.xH.SUB.2.O

(11) Method 1

(12) AlF.sub.3. 3 H.sub.2O (0.100 g, 0.73 mmol) was suspended in freshly distilled water (7 mL). Me.sub.3-tacn (0.125 g, 0.73 mmol) was then added and the pale yellow suspension was transferred into a Teflon container and loaded into a stainless steel high pressure vessel (Parr instrument company, part no 276AC-T304-04 1 101) and heated to 180° C. for 15 h. The vessel was then allowed to cool. A dark yellow-brown solution had formed. A small aliquot of the reaction solution was retained to grow crystals. For the remaining reaction mixture the volatiles were removed in vacuo, giving a light brown solid which was washed with hexane and filtered. The resulting white solid was dried in vacuo. Yield: 0.12 g, 53%.

(13) Anal. Calc. for C.sub.9H.sub.21Al F.sub.3N.sub.3. 3H.sub.2O: C, 34.9; H, 8.8; N, 13.6. Found: C, 34.3; H, 8.9; N, 14.7%.

(14) .sup.1H NMR (CD.sub.3CN, 298 K): δ 2.84-2.76 (m, [6H], CH.sub.2), 2.72-2.65 (m, [6H], CH.sub.2), 2.55 (s, [9H], CH.sub.3), 2.19 (s, H.sub.2O).

(15) IR (Nujol, v/cm.sup.−1): 3438 br (H.sub.2O), 1668 (H.sub.2O), 633, 614 (Al—F).

(16) Slow evaporation of the reaction solvent gave crystals suitable for X-ray diffraction.

(17) Method 2

(18) A solution of KF (0.058 g, 0.99 mmol) in water (2 mL) was added to a suspension of [AlCl.sub.3(Me.sub.3-tacn)] (Example 1, 0.100 g, 0.33 mmol) in MeCN (5 mL) at room temperature. A white precipitate formed initially which redissolved into solution after a few minutes. NMR spectroscopic data on the solution were as for Method 1.

EXAMPLE 4

Synthesis of [AlCl.SUB.3.(BzMe.SUB.2.-tacn)]

(19) AlCl.sub.3 (0.067 g, 0.50 mmol) was added to a solution of BzMe.sub.2-tacn (0.13 g, 0.50 mmol) in CH.sub.3CN (2 mL) at room temperature with stirring which led to the formation of precipitate. After 30 min the solvent was removed by filtration. The white precipitate was washed with small amount of CH.sub.2Cl.sub.2 solvent and dried in vacuo. Yield: 0.13 g, 68%.

(20) Anal. Calc. for C.sub.15H.sub.25AlCl.sub.3N.sub.3: C, 47.3; H, 6.6; N, 11.0. Found: C, 47.0; H, 6.6; N, 11.2.

(21) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 7.31 (m, [5H], ArH), 4.58 (s, [2H], Ar—CH.sub.2), 3.54 (m, [2H], tacn-CH.sub.2), 3.29 (m, [4H], tacn-CH.sub.2), 2.92 (s, [6H], CH.sub.3), 2.65 (m, [4H], tacn-CH.sub.2), 2.28 (m, [2H], tacn-CH.sub.2).

(22) IR (Nujol, v/cm.sup.−1): 398, 385 (Al—Cl).

EXAMPLE 5

Synthesis of [Albr.SUB.3.(BzMe.SUB.2.-tacn)]

(23) Al Br.sub.3 (0.133 g, 0.50 mmol) was added to a solution of BzMe.sub.2-tacn (0.13 g, 0.50 mmol) in CH.sub.2Cl.sub.2 (2 mL) at room temperature with stirring which immediately precipitated a white solid. After 30 min the solvent was removed by filtration. The white precipitate was washed with small amount of CH.sub.2Cl.sub.2 solvent and dried in vacuo. Yield: 0.19 g, 74%.

(24) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 7.31 (m, [5H], ArH), 4.75 (m, [2H], Ar—CH.sub.2), 3.72 (m, [2H], tacn-CH.sub.2), 3.46 (m, [4H], tacn-CH.sub.2), 3.04 (m, [6H], CH.sub.3), 2.70 (m, [4H], tacn-CH.sub.2), 2.33 (m, [2H], tacn-CH.sub.2).

(25) IR (Nujol, v/cm.sup.−1): 343, 325 sh (Al—Br).

EXAMPLE 6

Synthesis of [GaCl.SUB.3.(Me.SUB.3.-tacn)]

(26) Me.sub.3-tacn (0.09 g, 0.52 mmol) was added to a solution of GaCl.sub.3 (0.088 g, 0.50 mmol) in anhydrous CH.sub.2Cl.sub.2 (8 mL) at room temperature with stirring. After ca. 30 mins, a white precipitate started to appear. After 2 h stirring was stopped and the mixture was concentrated to afford more precipitate, the white powdered product was filtered from the solution and dried in vacuo. Yield: 0.110 g, 60%.

(27) Anal. Calc. for C.sub.9H.sub.21Cl.sub.3GaN.sub.3: C, 31.1; H, 6.1; N, 12.1. Found C, 31.2; H, 5.9; N, 12.1%.

(28) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 3.2 (br m, [6H], CH.sub.2), 2.85 (br s, [9H], Me), 2.6 (br m, [6H], CH.sub.2).

(29) IR (Nujol, v/cm.sup.−1): 290, 275 (Ga—Cl).

(30) An X-ray crystal structure was determined, see FIG. 2.

EXAMPLE 7

Synthesis of [GaF.SUB.3.(Me.SUB.3.-tacn)]

(31) Method as for [GaCl.sub.3(Me.sub.3-tacn)] (Example 6) but using Me.sub.3-tacn (0.086 g, 0.50 mmol) and GaBr.sub.3 (0.150 g, 0.50 mmol). White solid. Yield: 0.106 g, 45%.

(32) Anal. Calc. for C.sub.9H.sub.21Br.sub.3GaN.sub.3: C, 22.5; H, 4.4; N, 8.7. Found C, 22.4; H, 4.6; N, 8.6%.

(33) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 3.3 (br m, [6H], CH.sub.2), 2.9 (br s, [9H], Me), 2.7 (br m, [6H], CH.sub.2).

(34) Required for C.sub.9H.sub.21Br.sub.3GaN.sub.3: C, 22.49; H, 4.40; N, 8.74. Found C, 22.41; H, 4.62; N, 8.56%

EXAMPLE 8

Synthesis of [GaF.SUB.3.(Me.SUB.3.-tacn)].4H.SUB.2.O

(35) Method 1:

(36) [GaCl.sub.3(Me.sub.3-tacn)] (Example 6, 0.1 g, 0.28 mmol) was added to CH.sub.2Cl.sub.2 (8 mL) and stirred for ca. 15 mins., the solid mostly dissolved to give a clear solution. [NBu.sub.4]F in THF (1 mol dm.sup.−3, 0.84 mL, 0.84 mmol) was added to the mixture via syringe and the reaction was stirred for ca. 10 mins., giving a clear, colorless solution. The solution was filtered and the filtrate was taken to dryness in vacuo. The resulting colorless solid was re-dissolved in CH.sub.2Cl.sub.2, the solution was filtered and the CH.sub.2Cl.sub.2 was left to evaporate, giving a colorless solid product. Yield: 50%.

(37) Anal. Calc. for C.sub.9H.sub.21F.sub.3GaN.sub.3. 3 H.sub.2O: C, 30.7; H, 7.7; N, 11.9. Found: C, 30.6; H, 6.9; N, 11.0%.

(38) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 2.85-2.94 (br m, [6H], CH.sub.2), 2.67 (s, [9H], Me), 2.55-2.61 (br m, [6H], CH.sub.2, 2.17 (s, H.sub.2O).

(39) IR (Nujol, v/cm.sup.−1): 3481, 3429 (H.sub.2O), 1648 (H.sub.2O), 530, 492 (Ga—F).

(40) Method 2:

(41) [GaCl.sub.3(Me.sub.3-tacn)] (Example 6, 0.05 g, 0.15 mmol) was suspended in 5 mL anhydrous CH.sub.2Cl.sub.2. The suspension was treated with [NMe.sub.4]F (0.042 g, 0.45 mmol) and stirred at room temperature for 1 h. The [NMe.sub.4]Cl by-product was removed by filtration. The resulting colorless filtrate was treated with 5 mL hexane, resulting in a white precipitate which was isolated by filtration and dried in vacuo. Yield: 0.037 g, 74%.

(42) Spectroscopic data as for Method 1.

(43) Method 3:

(44) [GaCl.sub.3(Me.sub.3-tacn] (Example 6, 0.05 g, 0.15 mmol) was suspended in anhydrous MeCN (5 mL). A solution of KF (0.026 g, 0.45 mmol) in water (2 mL) was added drop-wise, leading to rapid dissolution and forming a colorless solution. The mixture was stirred for a further 1 h at room temperature.

(45) Spectroscopic data as for Method 1.

(46) Colourless crystals were grown from the CH.sub.2Cl.sub.2 solution of the product upon slow evaporation. An X-ray crystal structure was obtained, see FIG. 2.

EXAMPLE 9

Synthesis of [GaCl.SUB.3.(BzMe.SUB.2.-tacn)]

(47) BzMe.sub.2-tacn (0.125 g, 0.50 mmol) was added to a solution of GaCl.sub.3 (0.088 g, 0.50 mmol), 1:1, in dry CH.sub.2Cl.sub.2 (5-8 mL) at room temperature and stirred. After approximately 30 min. small quantities of a white precipitate started to form. After 12 hours, stirring was stopped and the mixture was concentrated by removal of CH.sub.2Cl.sub.2, which caused further precipitation of the product. The white product was filtered from the yellowish solution under nitrogen. The white powdered product was dried under vacuum for 2 h. Yield: 0.089 g, 42%.

(48) Anal. Calc. for C.sub.15H.sub.25Cl.sub.3GaN.sub.3: C, 42.5; H, 6.0; N, 9.9. Found C, 42.2; H, 6.0; N, 9.6%.

(49) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 7.30 (br m, [5H], ArH), 4.71 (s, [2H], Ar—CH.sub.2), 3.67 (br, [.sup.2H], tacn-CH.sub.2), 3.20 (br, [2H], tacn-CH.sub.2), 2.92 (br s, [6H], CH.sub.3), 2.75 (br m, [2H], tacn-CH.sub.2), 2.62 (br m, [2H], tacn-CH.sub.2), 2.40 (br m, [2H], CH.sub.2).

(50) IR (Nujol, v/cm.sup.−1): 301, 280 (Ga—Cl).

EXAMPLE 10

Synthesis of [GaF.SUB.3.(BzMe.SUB.2.-tacn)].xH.SUB.2.O

(51) [GaCl.sub.3(BzMe.sub.2-tacn)] (Example 9, 0.05 g, 0.10 mmol) was suspended in 5 mL anhydrous CH.sub.2Cl.sub.2. The suspension was treated with [NMe.sub.4]F (0.03 g, 0.30 mmol) and stirred at room temperature for 1 h. The [NMe.sub.4]Cl by-product was removed by filtration. The resulting colorless filtrate was treated with 5 mL anhydrous hexane, forming a white precipitate which was isolated by filtration and dried in vacuo. Yield: 0.035 g, 80%.

(52) .sup.1H NMR (D.sub.2O, 298 K): δ 7.30 (m, [5H], ArH), 4.73 (s, [2H], Ar—CH.sub.2), 3.17 (m, [4H], tacn-CH.sub.2), 2.88 (m, [4H], tacn-CH.sub.2), 2.73 (s, [6H], CH.sub.3), 2.36 (m, [4H], tacn-CH.sub.2), 2.25 (s, H.sub.2O).

(53) IR (Nujol, v/cm.sup.−1): 3390, 1654 (H.sub.2O) 526, 515 (Ga—F).

EXAMPLE 11

Synthesis of [InCl.SUB.3.(Me.SUB.3.-tacn)]

(54) Me.sub.3-tacn (0.086 g, 0.50 mmol) was added to a solution of InCl.sub.3 (0.110 g, 0.50 mmol), 1:1, and dry CH.sub.2Cl.sub.2 (5-8 mL) at room temperature and stirred. After approximately 30 min. a white precipitate started to form. After 2 hours, stirring was stopped and the mixture was concentrated which caused further precipitation of the product. The white product was filtered from solution under nitrogen and was dried under vacuum for 2 h. Yield: 0.113 g, 57%.

(55) Anal. Calc. for C.sub.9H.sub.21Cl.sub.3InN.sub.3: C, 27.5; H, 5.4; N, 10.7. Found C, 27.8; H, 5.4; N, 10.9%.

(56) .sup.1H NMR (CDCl.sub.3, 298 K): δ 3.1 (br m, [6H], CH.sub.2), 2.8 (br m, [15H], Me and CH.sub.2).

(57) IR (Nujol, v/cm.sup.−1): 287, 269 (In—Cl).

EXAMPLE 12

Synthesis of [InBr.SUB.3.(Me.SUB.3.-tacn)]

(58) Me.sub.3-tacn (0.087 g, 0.50 mmol) was added to a solution of InBr.sub.3 (0.177 g, 0.50 mmol), 1:1, in dry CH.sub.2Cl.sub.2 (5-8 mL) at room temperature and stirred. After approximately 30 minutes a white precipitate had started to form. After 2 h, stirring was stopped and the mixture was concentrated by removal of CH.sub.2Cl.sub.2, which caused further precipitation of the product. The solid product was filtered from the colourless filtrate under nitrogen and dried under vacuum for 2 h. Yield: 0.162 g, 68%.

(59) Anal. Calc. for C.sub.9H.sub.21Br.sub.3InN.sub.3: C, 20.5; H, 4.0; N, 8.0. Found C, 19.8; H, 4.0; N, 7.4%.

(60) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 3.18 (br m, [6H], CH.sub.2), 2.78 (br s, [9H], Me), 2.67 (br m, [6H], CH.sub.2).

EXAMPLE 13

Synthesis of [InF.SUB.3.(Me.SUB.3.-tacn)].H.SUB.2.O

(61) Method 1:

(62) [InCl.sub.3(Me.sub.3-tacn)] (Example 11, 0.214 g, 0.54 mmol) was added to CH.sub.2Cl.sub.2 (8 mL) and stirred for ca. 15 mins., this gave a cloudy suspension. [N.sup.nBu.sub.4]F in THF (1 mol dm.sup.−3, 1.63 mL, 1.63 mmol) was added to the mixture via a syringe and stirred for ca. 2 h. The solution was filtered and the white precipitate collected, washed with hexane and dried in vacuo. Yield: 0.150 g, 70%.

(63) Anal. Calc. for C.sub.9H.sub.21F.sub.3InN.sub.3—H.sub.2O: C, 29.9; H, 6.4; N, 11.6. Found: C, 29.9; H, 6.1; N, 11.5%.

(64) .sup.1H NMR (CD.sub.2Cl.sub.2, 298 K): δ 3.09-3.15 (br m, [6H], CH.sub.2), 2.93 (m, [9H], Me), 2.72-2.82 (br m, [6H], CH.sub.2), 2.19 (s, H.sub.2O).

(65) IR (Nujol, v/cm.sup.−1): 3392 br (H.sub.2O), 1669 (H.sub.2O), 479, 462, 443 (In—F).

(66) Colorless crystals were grown from the CH.sub.2Cl.sub.2 solution of the product upon slow evaporation.

(67) Method 2:

(68) [InCl.sub.3(Me.sub.3-tacn)] (Example 11, 0.060 g, 0.17 mmol) was suspended in 5 mL anhydrous CH.sub.2Cl.sub.2. The suspension was treated with [NMe.sub.4]F (0.047 g, 0.51 mmol) and stirred at room temperature for 1 h. The [NMe.sub.4]Cl by-product was removed by filtration. The resulting colorless filtrate was treated with 5 mL anhydrous hexane, forming a white precipitate which was isolated by filtration and dried in vacuo. Yield: 0.044 g, 76%.

(69) Spectroscopic data as for Method 1.

(70) Colourless crystals were grown from the CH.sub.2Cl.sub.2 solution of the product upon slow evaporation.

EXAMPLE 14

Synthesis of [InCl.SUB.3.(BzMe.SUB.2.-tacn)]

(71) BzMe.sub.2-tacn (0.125 g, 0.50 mmol) was added to a solution of InCl.sub.3 (0.110 g, 0.50 mmol), 1:1, in dry CH.sub.2Cl.sub.2 (5-8 mL) at room temperature and stirred. After approximately 30 minutes some white precipitate had started to form, turning the mixture cloudy. After 2 h, stirring was stopped and the mixture was concentrated by removal of CH.sub.2Cl.sub.2, which caused further precipitation of the product. The white product was filtered from the yellow solution under nitrogen and was dried under vacuum for 2 h. Yield: 0.093 g, 40%.

(72) Anal. Calc. for C.sub.15H.sub.25Cl.sub.3InN.sub.3: C, 38.5; H, 5.4; N, 9.0. Found C, 38.8; H, 5.8; N, 8.7%.

(73) .sup.1H NMR (CD.sub.3CN, 298 K): 7.2-7.4 (m, [5H], ArH), 4.37 (s, [2H], Ar—CH.sub.2), 3.45 (br, [.sup.2H], tacn-CH.sub.2), 3.10 (br, [2H], tacn-CH.sub.2), 2.80 (s, [6H], CH.sub.3), 2.75 (br m, [2H], tacn-CH.sub.2), 2.60 (br m, [2H], tacn-CH.sub.2), 2.40 (br m, [2H], CH.sub.2).

(74) IR (Nujol, v/cm.sup.−1): 289, 271 (In—Cl).

(75) Crystals formed from the CH.sub.2Cl.sub.2 solution of the product stored in the freezer at −18° C.

EXAMPLE 15

Synthesis of [InF.SUB.3.(BzMe.SUB.2.-tacn)]

(76) [InCl.sub.3(BzMe.sub.2-tacn)] (Example 14, 0.06 g, 0.10 mmol) was suspended in 5 mL anhydrous CH.sub.2Cl.sub.2. The suspension was treated with [NMe.sub.4]F (0.03 g, 0.30 mmol) and stirred at room temperature for 1 h. The [NMe.sub.4]Cl by-product was removed by filtration. The resulting colorless filtrate was treated with 5 mL anhydrous hexane, forming in a white precipitate which was isolated by filtration, washed with hexane and dried in vacuo. Yield: 0.02 g, 48%.

(77) .sup.1H NMR (CD.sub.3CN, 298 K): 7.37 (m, [5H], ArH), 4.37 (s, [2H], Ar—CH.sub.2), 3.08 (m, [6H], CH.sub.3), 2.91 (m, [4H], tacn-CH.sub.2), 2.80 (m, [4H], tacn-CH.sub.2), 2.64 (m, [4H], tacn-CH.sub.2).

(78) IR (Nujol, v/cm.sup.−1): 3450 v br (H.sub.2O), 1651 (H.sub.2O), 481, 463 (In—F).

(79) Crystals were obtained by cooling the filtrate in the freezer.

EXAMPLE 16

.SUP.18.F-Radiolabelling of [GaCl.SUB.3.(BzMe.SUB.3.-tacn)]

(80) [GaCl.sub.3(BzMe.sub.2-tacn)] (Example 9; 1 mg, 2.36 μmol) was dissolved in 0.5 mL MeCN/0.1 mL H.sub.2O. The solution was added to 0.4 ml of an aqueous solution containing [.sup.18F]fluoride (100 to 400 MBq) and [.sup.19F]KF (7.05 μmol), and the vial was left to stand at room temperature for 30 to 60 minutes. Subsequent HPLC confirmed 20 to 40% incorporation of .sup.18F into the metal complex.

(81) HPLC: Luna 5μ C18(2) 150×4.6 mm (Mobile phase A=50 mM ammonium acetate;

(82) Mobile phase B=100% MeCN). Flow rate 1 mL/min.

(83) 0 min (10% B), 15 min (90% B), 20 min (90% B), 21 min (10% B), 26 min (10% B).

(84) TABLE-US-00001 TABLE 1 Summary of NMR spectroscopic data. δ.sup.27Al/.sup.71Ga/.sup.115In/ δ.sup.19F{.sup.1H} Complex ppm; (w.sub.1/2/Hz) (ppm) Solvent [AlF.sub.3(Me.sub.3-tacn)] 19.0 (60) −176.1 MeCN 18.5 (52) −169.9 D.sub.2O [AlCl.sub.3(Me.sub.3-tacn)] 34.5 (30) — CH.sub.2Cl.sub.2 [AlBr.sub.3(Me.sub.3-tacn)] 18.9 (80) — CH.sub.2Cl.sub.2 [GaF.sub.3(Me.sub.3-tacn)] 42.0 −180.9 (two br q) CH.sub.2Cl.sub.2 (q, .sup.1J.sub.GaF ~490 Hz) −173 (br) D.sub.2O 44.6 (br q) [GaCl.sub.3 (Me.sub.3-tacn)] 93.9 (60) — CH.sub.2Cl.sub.2 [GaBr.sub.3(Me.sub.3-tacn)] −29.3 (180) — MeCN [InF.sub.3(Me.sub.3-tacn)] 64 −215 (br) MeCN (q, .sup.1J.sub.InF ~600 Hz) −192.5 (br) D.sub.2O n.o. [InCl.sub.3(Me.sub.3-tacn)]   268 (750) — CH.sub.2Cl.sub.2 [InBr.sub.3(Me.sub.3-tacn)] n.o..sup.a — MeCN [AlF.sub.3(BzMe.sub.2-tacn)] 20.3 (m) −149.4 (m, F), MeCN −150.4 (m, 2F) [AlCl.sub.3(BzMe.sub.2-tacn)] 36.5 (45) — CH.sub.2Cl.sub.2 [AlBr.sub.3(BzMe.sub.2-tacn)] 20.1 (35) — CH.sub.2Cl.sub.2 [GaF.sub.3(BzMe.sub.2-tacn)] 44.9 −172.8 (br) D.sub.2O (q .sup.1J.sub.GaF ~445 Hz) [GaCl.sub.3(BzMe.sub.2-tacn)]  92.8 (360) — MeCN [InF.sub.3(BzMe.sub.2-tacn)] n.o..sup.a −220 (br) MeCN [InCl.sub.3(BzMe.sub.2-tacn)]   265 (2200) — MeCN .sup.an.o. = not observed