# US 5,700,446 A · Synthesis of ferrocenyl phenyltropane analogs and their radio-transformation to technetium neuroprobes for mapping monoamine reuptake sites

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- Number: US 5,700,446 A
- Document ID: US5700446A
- Status: Granted
- Kind: A
- Application number: 08/662,656
- Filed: 1996-06-13
- Granted: 1997-12-23
- Earliest claimed: 1996-06-13
- Assignees: Neuro Imaging Technologies, LLC
- Inventors: John L. Neumeyer; Gilles Tamagnan; Yigong Gao
- Web page: https://patentgrep.com/patent/US5700446A

## CPC

- C07F 17/00: Metallocenes
- A61K 51/0487: {Metallocenes, i.e. complexes based on a radioactive metal complexed by two cyclopentadienyl anions}
- A61K 2123/00: Preparations for testing in vivo
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Neuroprobes that include rhenium, manganese, and technetium for use in mapping monoamine reuptake sites are disclosed. Non-radioactive tricarbonylrheniumcyclopentadienyl (TRCp) or non-radioactive tricarbonylmanganesecyclopentadienyl (TMCp) phenyltropane analogs are synthesized for use as testing surrogates for radioactive technetium congeners. Ferrocenyl analogs of phenyltropane are disclosed as useful precursors for the preparation of novel tricarbonyltechnetiumcyclopentadienyl (TTCp) phenyltropane analogs in radioactive form.

## Claims

### Claim 1

A neuroprobe for mapping monoamine reuptake sites, the neuroprobe having the formula: ##STR16## wherein: X=F, Cl, Br, I, H or alkyl;
X'=F, Cl, Br, I, H or alkyl;
R=alkyl, halogen substituted alkyl, cycloalkyl, halogen substituted cycloalkyl, alkenyl, halogen substituted alkenyl, aryl or halogen substituted aryl; and
R'=--(CH.sub.2).sub.n Y, wherein Y=--O--C(O)--Z, --C(O)--Z, or --NR"--C(O)--Z; and n=1-6; and wherein further R"=alkyl, cycloalkyl or H; and Z= ##STR17## wherein M=rhenium or an isotope of rhenium, manganese or an isotope of manganese, or an isotope of technetium.

### Claim 2 (depends on 1)

The neuroprobe of claim 1, wherein X is in the meta or para position.

### Claim 3 (depends on 1)

The neuroprobe of claim 1, wherein X' is in the metal or para position.

### Claim 4 (depends on 1)

The neuroprobe of claim 1, wherein said isotope of Tc is .sup.99m Tc.

### Claim 5

A neuroprobe for mapping monoamine reuptake sites, the neuroprobe having the formula: ##STR18## wherein: X=F, Cl, Br, I, H or alkyl;
X'=F, Cl, Br, I, H or alkyl;
R'=alkyl, halogen substituted alkyl, cycloalkyl, halogen substituted cycloalkyl, alkenyl, halogen substituted alkenyl, aryl or halogen substituted aryl; and
R=--(CH.sub.2).sub.n Y, wherein Y=--O--C(O)--Z, --C(O)--Z, or --NR"--C(O)--Z; and n=1-6; and wherein further R"=alkyl, cycloalkyl or H; and Z= ##STR19## wherein M=rhenium or an isotope of rhenium, manganese or an isotope of manganese, or an isotope of technetium.

### Claim 6 (depends on 5)

The neuroprobe of claim 5, wherein X is in the meta or para position.

### Claim 7 (depends on 5)

The neuroprobe of claim 5, wherein X' is in the meta or para position.

### Claim 8 (depends on 5)

The neuroprobe of claim 5, wherein said isotope of Tc is .sup.99m Tc.

### Claim 9

A neuroprobe for mapping monoamine reuptake sites, the neuroprobe having the formula: ##STR20## wherein: X=F, Cl, Br, I, H or alkyl;
X'=F, Cl, Br, I, H or alkyl;
R'=alkyl, halogen substituted alkyl, cycloalkyl, halogen substituted cycloalkyl, alkenyl, halogen substituted alkenyl, aryl or halogen substituted aryl; and
R=--(CH.sub.2).sub.n Y, wherein Y=--O--C(O)--Z, --C(O)--Z, or --NR"--C(O)--Z; and n=14 6; and wherein further R"=alkyl, cycloalkyl or H; and Z= ##STR21## wherein M=rhenium or an isotope of rhenium, manganese or an isotope of manganese, or an isotope of technetium.

### Claim 10 (depends on 9)

The neuroprobe or claim 9, wherein X is in the meta or para position.

### Claim 11 (depends on 9)

The neuroprobe of claim 9, wherein X' is in the meta or para position.

### Claim 12 (depends on 9)

The neuroprobe of claim 9, wherein said isotope of Tc is .sup.99m Tc.

### Claim 13

A compound of the formula having the core structure: ##STR22## wherein: X=F, Cl, Br, I, H or alkyl;
X'=F, Cl, Br, I, H or alkyl;
R=alkyl, halogen substituted alkyl, cycloalkyl, halogen substituted cycloalkyl, alkenyl, halogen substituted alkenyl, aryl or halogen substituted aryl; and
R'=--(CH.sub.2).sub.n Y, wherein Y=--O--C(O)--Z, --C(O)--Z, or --NR"--C(O)--Z; and n=1-6; and wherein further R"=alkyl, cycloalkyl or H; and Z= ##STR23## wherein Z is attached to two of said core structure (I), or wherein Z= ##STR24## wherein Z is attached to one of said core structure (I).

### Claim 14 (depends on 13)

The neuroprobe of claim 13, wherein X is in the meta or para position.

### Claim 15 (depends on 13)

The neuroprobe of claim 13, wherein X' is in the meta or para position.

### Claim 16 (depends on 13)

The neuroprobe of claim 13, wherein said isotope of Tc is .sup.99m Tc.

### Claim 17

A compound of the formula having the core structure: ##STR25## wherein: X=F, Cl, Br, I, H or alkyl,
X'=F, Cl, Br, I, H or alkyl;
R'=alkyl, halogen substituted alkyl, cycloalkyl, halogen substituted cycloalkyl, alkenyl, halogen substituted alkenyl, aryl or halogen substituted aryl; and
R=--(CH.sub.2).sub.n Y, wherein Y=--O--C(O)--Z, --C(O)--Z, or --NR"--C(O)--Z; and n=1-6; and wherein further R"=alkyl, cycloalkyl or H; and Z= ##STR26## wherein Z is attached to two of said core structure (I), or wherein Z= ##STR27## wherein Z is attached to one of said core structure (I).

### Claim 18 (depends on 17)

The neuroprobe of claim 17, wherein X is in the meta or para position.

### Claim 19 (depends on 17)

The neuroprobe of claim 17, wherein X' is in the meta or para position.

### Claim 20 (depends on 17)

The neuroprobe of claim 17, wherein said isotope of Tc is .sup.99m Tc.

### Claim 21

A compound of the formula having the core structure: ##STR28## wherein: X=F, Cl, Br, I, H or alkyl;
X'=F, Cl, Br, I, H or alkyl;
R'=alkyl, halogen substituted alkyl, cycloalkyl, halogen substituted cycloalkyl, alkenyl, halogen substituted alkenyl, aryl or halogen substituted aryl; and
R=--(CH.sub.2).sub.n Y, wherein Y=--O--C(O)--Z, --C(O)--Z, or --NR"--C(O)--Z; and n=1-6; and wherein further R"=alkyl, cycloalkyl or H; and Z= ##STR29## wherein Z is attached to two of said core structure (I), or wherein Z= ##STR30## wherein Z is attached to one of said core structure (I).

### Claim 22 (depends on 21)

The neuroprobe of claim 21, wherein X is in the meta or para position.

### Claim 23 (depends on 21)

The neuroprobe of claim 21, wherein X' is in the meta or para position.

### Claim 24 (depends on 21)

The neuroprobe of claim 21, wherein said isotope of Tc is .sup.99m Tc.