Phosphodiesterase 1-targeting tracers and methods

Abstract

Tracers targeting phosphodiesterase 1 for use in gamma radiation detection-based diagnostic techniques, particularly gamma-emitter labeled tracers for SPECT and positron emitter-labeled compositions for PET are disclosed. Radio-labeled multiple novel scaffolds as PDE1 inhibitors such as substituted pyrazolo-pyrimidin-4-one derivatives, biomarkers for phosphodiesterase 1 [PDE1) in vivo, methods for developing novel therapies for PDE1-implicated conditions such as pulmonary arterial hypertension (PAH), Central Nervous System (CNS) and Cardiovascular (CV) disorders, and methods of detection and treatment are also disclosed.

I/we claim: 
     
         1 . A radiolabeled PDE1 inhibitor. 
     
     
         2 . A radiotracer composition for use in gamma radiation-based diagnostic imaging comprising:
 a) a phosphodiesterase 1-selective ligand in free, salt or prodrug form selected from:   i)7,8-dihydro-[1H or 2H]-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one;   ii)7,8,9-trihydro-[1H or 2H]-pyrimido [1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one;   iii) 3-(optionally hetero)arylamino-[2H]-pyrazolo[3,4-d] pyrimidine-4,6(5H, 7H)-dione; and   iv)(6aR*,9aS*)-3-(phenylamino)-5-6a,7,8,9,9a-hexahydro-5-methylcyclopent [4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(1H or 2H)-one;   wherein each of (i), (ii), (iii) and (iv) are substituted at the 1- or 2-position with C2-9 alkyl, C 3 - 9  cycloalkyl, heteroarylalkyl, or substituted arylalkyl; and   b) a radionuclide chemically bound to said ligand.   
     
     
         3 . The composition of  claim 2 , wherein the radionuclide is selected from Carbon-11, Fluorine-18, Technetium-99m, Indium-111 and Iodine-123. 
     
     
         4 . A method of selective reversible binding and mapping of functional phosphodiesterase 1 activity in vivo in tissue and/or organ of interest using positron emission tomography which comprises:
 (a) administering an effective amount of a compound of  claim 1  to the subject, and then   (b) allowing a period of time sufficient for the radiotracer to effectively associate with phosphodiesterase 1 in the tissues and organs of interest, and then   (c) analyzing the tissues and organs of interest using positron emission tomography.   
     
     
         5 . A therapeutic treatment for phosphodiesterasel-associated conditions comprising:
 administering the radiotracer composition of  claim 1  to a subject, then imaging the subject with a positron emission tomography device, then administering a phosphodiesterasel inhibitor which does not contain a radionuclide to the subject at a given dose, then   imaging the subject with a positron emission tomography device, then comparing the data thus obtained, and   assessing the effective delivery of the phosphodiesterasel inhibitor to tissue(s) of interest in the phosphodiesterase1-associated condition.   
     
     
         6 . The method of  claim 5  wherein the condition is selected from the group consisting of Pulmonary Arterial Hypertension, Central Nervous System Disorders and Cardiovascular Disorders.