The design of novel detection method of phosphorylated CREB is crucial for creation of the detection method with higher sensitivity, selectivity, shorter response time and lower price. In this work novel optical and nonlinear optical detection methods for phosphorylated CREB are proposed and confirmed. We have applied two approaches to solve this problem. The first one - completely novel OCSM with higher coordination selectivity is designed. The second one - two different absorption spectral peaks are used to measure the phosphorylated level of CREB. The proposed approach demonstrates a great advantage in sensitivity, selectivity and response time with respect to the existed. The principal innovation of this approach is based on the supra-molecular interactions between the designed organic conjugated small molecule (OCSM), Zr4+ ion and phosphorylated CREB. Due to the strong and special interaction between zr(4+) ion and phosphate groups, such method shows an enhancement of the sensitivity. As a nonlinear optical method is proposed to use the second harmonic generation (SHG).